Confernce Book 2013

1www.asyn-parkinsonconference.ae

International Conference on “Alpha-Synuclein in Parkinson’s Disease and Related Neurodegenerative Diseases: From Mechanisms to Therapeutic Strategies”

www.asyn-parkinsonconference.ae

Congress Secretariat: MCI Middle East, United Arab Emirates, Tel: +971 4 311 6300, Fax: +971 4 311 6301, E-mail:[email protected]

Congress Book

Associated withOrganized by

College of Medicine and Health Sciences

Supported by

Parkinson’s Disease Pre-Conference Workshop 1st March 2013

5 CME Hours Accredited by DHA & UAEU

10 CME Hours Accredited by DHA & UAEUMain Conference

March 01 – 03, 2013 | Gloria Hotel, Dubai, UAE

2 www.asyn-parkinsonconference.ae

His Highness Sheikh Khalifa Bin Zayed Al NahyanPresident of the U.A.E


His Highness Sheikh Mohammed Bin Rashid Al MaktoumVice President, Prime Minister and Ruler of Dubai


His Highness Sheikh Hamdan Bin Rashid Al MaktoumDeputy Ruler of Dubai, Minister of Finance, UAE

President of Dubai Health Authority


Welcome Message ............................................................ 06

Committees ....................................................................... 07 - 08

Venue & Exhibition Layout .................................................. 09

Program at a Glance ........................................................... 10

Sceintific Program ............................................................... 11 - 14

Faculty Profile ................................................................... 15 - 37

Abstracts ........................................................................... 40 - 62

Poster Presentations............................................................ 64 - 85

Sponsons Profiles ................................................................. 86 - 87

Experience Dubai ................................................................. 88 - 89

Table of Contents


Dear Colleagues,

Welcome to Dubai, United Arab Emirates. The Organizing Committee of the Alpha-Synuclein

in Parkinson’s Disease & Related Neurodegenerative Diseases: From Mechanisms to Thera-

peutic Strategies, (1st – 3rd March 2013) Dubai, United Arab Emirates, has great pleasure in

inviting you to participate in this International Conference.

The aim of the Conference is to bring together neuroscientists from the region and the rest of

the world to discuss the advances of alpha-synuclein in health and diseases. At the meeting

we will debate current issues and challenges in structures and mechanisms involved diseases,

new strategies for early disease detection (Biomarkers) to allow future neuroprotective and

restorative treatment, and new therapeutic strategies for Parkinson disease, dementia and

multiple system atrophy.

The conference will present a good balance between the recent advances in basic science and

translational research.

Dubai offers a kaleidoscope of attractions for visitors. In a single day, you can experience eve-

rything from rugged mountains and awe-inspiring sand dunes to sandy beaches and lush green

parks, from dusty villages to luxurious residential districts and from ancient houses with wind

towers to ultra-modern shopping malls. Dubai’s charm has attracted many visitors and made

their stay one of the most memorable. March weather is perfect for several outdoor activities

and provides an opportunity to explore the city. The weather during March is very pleasant with

average temperature is 28 °C (82 °F), with moderate heat and humidity.

Registration fees have been kept affordably low in order to encourage participation from every-

where especially from young practitioners and scientists in the region.

We shall strive to make your stay in Dubai comfortable and fruitful. We look forward to meeting

you in Dubai in March, 2013.

Asyn – Parkinson 2013 Organizing Committee!

Welcome Message


Omar M. El-AgnafProfessor

Department of BiochemistryUnited Arab Emirates University, UAE

Wei-Ping GaiSenior Lecturer

Flinders University of South AustraliaAustralia

Leonidas StefanisProfessor

Academy of AthensGreece


Department of BiochemistryUnited Arab Emirates University,

UAE

Conference Chair

Organising & Scientific Committee

Poul Henning Jensen Vice Chair Professor

Department of BiomedicineAarhus University, Denmark

Lashuel HilalAssociate Professor

Brain Mind Institute, École Polytechnique Fédérale de Lausanne

Switzerland

Gregor WenningProfessor

University of InnsbruckAustria

Glenda HallidayProfessor

University of New South Wales

Sydney, Australia

Philipp KahleProfessor

Hertie Institute for Clinical Brain Research

Tübingen, Germany

Suhail AlruknNeurology Consultant

Rashid HospitalDubai, UAE

Committees


Committees


Department of BiochemistryUnited Arab Emirates University, UAE

Jihad InshashiNeurology Consultant


Regional Organising Committee

Suhail AlruknNeurology Consultant


Abu Baker Almadani Neurology Consultant



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Scientific Program

Parkinson’s Disease Pre-Conference Workshop Program

Friday, 1st March 2013

08:00 – 09:00 Registration

09:00 – 09:15 Opening Speech Suhail Al-Rukn, UAE

Parkinson’s Disease Genetics and Pathogenesis - I Chairperson: Abdu Adem, UAE

09:15 – 9:45 Where we are with Genetics in Parkinson’s Disease Thomas Gasser, Germany

9:45 – 10:15 Role of LRRK2 Gene in Parkinson’s Disease Patient North Africa Faycal Hentati, Tunisia

10:15 - 10:30 Panel Questions

10:30 – 10:45 Coffee Break

Parkinson’s Disease Genetics and Pathogenesis - II Chairperson: Suhail Al-Rukn, UAE

10:45 – 11:15 Neuropathology of Parkinson’s Disease and Related Disorders Glenda Halliday, Australia

11:15 – 11:45 Clinical use of Biomarkers for Early Diagnosis of PD, Lessons from AD. Lucilla Parnetti, Italy

11:45 - 12:00 Panel Questions

12:00 – 14:00 Lunch Break

Clinical Presentation - Part I Chairperson: Abu-Baker Al Madani, UAE

14:00 – 14:30 Update on PD: New Insight and Management Michael G. Schlossmacher, Canada

14:30 – 15:00 Motor and Non-Motor Wearing off in Parkinson’s Disease Boulus-Paul Bejjani, Lebanon

15:00 – 15:30 DBS in PD, Still Need Better Management Strategy Samir Atweh, Lebanon

15:30 – 16:00 Challenging Cases of Movement Disorders and DBS Solutions Boulus-Paul Bejjani, Lebanon

16:00 – 16:10 Panel Questions


Clinical Presentation - Part II Chairperson: Jihad Inshashi, UAE

16:30 – 16:50 Sleep Disorders with Parkinson’s Disease Suhail Al-Rukn, UAE

16:50 – 17:10 Managing Cognitive and Behavioral Changes in PD Abu-Baker Al Madani, UAE

17:10 – 17:50 What to do with Patients who have Atypical Parkinsonism Michael G. Schlossmacher, Canada

17:50 – 18:00 Panel Questions


Scientific Program

09:00 – 09:05 Omar M El-Agnaf, UAE, 09:05 – 09:15 Opening Ceremony Mohamed Yousif Baniyas, Provost UAE University, UAE

09:15 - 09:45 Plenary Session John Hardy, UK

10:00 - 11:30 New Concepts from Genetics

10:00 - 10:15 Genetic Modifiers of Sporadic PD: Update on GWAS Thomas Gasser, Germany

10:15 - 10:30 New late-onset Autosomal Dominant Genes (EIF4GI & VPS35) – Matt Farrer, Canada What do they tell us and how do they fit in with AS and LRRK2?

10:30 - 10:45 LRRK2 and PD in Tunisia Faycal Hentati, Tunisia

10:45 - 11:15 Round Table: Are we Closer to a Biological Model from Genetics? Chairs: John Hardy, UK & Philipp Kahle, Germany

11:15 - 11:45 Coffee Break

11:45 - 13:15 Synapses and Parkinson’s Disease

11:45 - 12:00 Neuropathological Features of Synucleinopathies Wei-Ping Gai, Australia

12:00 - 12:15 Synapses are Where it all starts? Evidence from Human & Animal Studies Maria Gracia Spillanti, UK

12:15 - 12:30 Subsequent Steps to Neurodegeneration - Synapses First & Then What? Michael Lee, USA

12:30 - 12:45 Where does Ser129 Phosphorylation fit in the path? Philipp Kahle, Germany

12:45 - 13:15 Round Table: Do we know where the Problem begins? Chairs: John Trojanowski, USA & Seung Jae Lee, Korea

13:15 – 14:30 Lunch Break

14:30 - 16.00 AS Structure (Native State) & Toxicity - What else is new?

14:30 - 14:45 AS Tetramers, Function & Dysfunction Quyen Hoang, USA

14:45 - 15:00 AS Structure/Function & Dysfunction David Elizer, USA

15:00 - 15:15 AS Aggregates/Seeds (Fragments, Function & Dysfunction) Virginia Lee, USA

15:15 - 15:30 AS Phosphorylation, Function and Dysfunction Hilal Lashuel, Switzerland

15:30 - 16:00 Round Table: Do we know the structural changes making AS toxic? Chairs: Pamela McLean, USA; Glenda Halliday, Australia


Saturday, 2nd March 2013


Scientific Program

16:30 - 18:15 AS Interactions, Catabolism and Secretion

16:30 - 16:45 Vesicle Selectivity: Membrane Sensing & Dynamics David Elizer, USA

16:45 - 17:00 Catabolism Through Autophagy Leonidas Stefanis, Greece

17:15 - 17:30 Proteosome Role in Catabolism Pamela McLean, USA

17:30 - 17:45 Regulation of AS secretion Takafumi Hasegawa, Japan

17:45 - 18:15 Round Table: Do we know how the Problem is Transmitted? Chairs: Omar M El-Agnaf,UAE & Michael Lee, USA

18:15 - 19:45 Poster Viewing

09:00 - 10:30 Biomarkers

09:00 - 09:15 CSF Alpha-Synuclein in Neurodegenerative Disorders: An Overview Omar M El-Agnaf, UAE

09:15 - 09:30 Quantification of Total Alpha-Synuclein in Cerebrospinal Fluid of Different Cohorts Britt Mollenhauer, Germany

09:30 - 09:45 Parkinson’s Biomarkers - Transition from CSF to Peripheral Body Fluids Jing Zheng, USA

09:45 - 10:00 MJFF Parkinson’s Progression Markers Initiative John Trojanowski, USA

10:00 - 10:30 Round Table: What is the best Approach to Measure AS Pathologies? Chairs: Michael Schlossmacher, Canada & Poul Henning Jensen, Denmark

10:30 - 11:00 Coffee Break

11:00 - 12:30 Non-Neuronal AS Pathology

11:00 - 11:15 Extracellular AS Seung Jae Lee, Korea

11:15 - 11:30 Astrocytes Glenda Halliday, Australia

11:30 - 11:45 Oligodendroglia Nadia Stefanova, Austria

11:45 - 12:00 Subsequent Steps to AS Aggregation in MSA Poul Henning Jensen, Denmark

12:00 - 12:30 Round Table: Do we Understand the Involvement of Non-Neuronal Cells and Extracellular Mechanisms? Chairs: Gregor Wenning, Austria & Jing Zheng, USA

12:30 - 13:30 Lunch Break

13:30 - 15:00 AS Therapeutics

13:30 - 13:45 Targeting AS Levels through Lysosomal Enzymes (CTSD,GBA1) Michael Schlossmacher, Canada

Sunday, 3rd March 2013


Scientific Program

13:45 - 14:00 Targeting Native AS using Pharmacological Chaperones and Aggregation Lisa McConlogue, USA Inhibitors

14:00 - 14:15 Targeting HSPs to Modulate AS Toxicity Pamela McLean, USA

14:15 - 14:30 Using Immunization to Counteract AS toxicity Karina Fog, Denmark

14:30 - 15:00 Round Table: What is the best Approach to Attack Synucleinopathies? Chairs: Hilal Lashuel, Switzerland & Leonidas Stefanis, Greece

15:00 - 16:00 Round Table: Facing Current Challenges and Future Perspectives Chairs: Virginia Lee, Glenda Halliday, Michael Schlossmacher and Matt Farrer


Faculty Profile

Brit MollenhauerAssistant Paracelsus Elena-Klinik Germany

Abu Baker Almadani Neurology ConsultantRashid HospitalDubai, UAE

Dr. Brit Mollenhauer graduated from Medical School at Georg-August University Goettingen, Ger-many in 2000. During residency training in Neurology from 2000-2005 in Goettingen, Dr. Mollen-hauer was also a member of the National Creutzfeldt-Jakob Disease Surveillance Center under the mentorship of Prof. Sigrid Poser, where she focused her research activities on the differential diag-noses of prion diseases, with special interest on dementia with Lewy Bodies, Parkinson disease and cerebrospinal fluid biomarker in collaboration with Dres J. Wiltfang and M. Otto. After completing the neurology training in 2005 Dr. Mollenhauer received a research fellowship by the “Stifterverband fuer die Deutsche Wissenschaft” to visit Harvard University and laboratory of Dr. M. Schlossmacher in Boston, USA, where she studied biomarker development and cerebrospinal fluid alpha-synuclein (2005-2007). Since June 2007 she holds a position as Assistant Professor in Neurology at Georg-August University Goettingen, Germany and the Movement Disorder Paracelsus-Elena Klinik, Kas-

Dr. Abubaker has recently joined the American Center for Psychiatry & Neurology in Dubai as a Con-sultant Neurologist. Dr. Abubaker still holds position at Rashid Hospital as a consultant of neurology since 2009. He has participated in the development of stroke program and actively developed the department of neurology at Rashid Hospital. He is very active in teaching and actively involved in the development of Neurology residency program.

Dr. Abubaker completed his MD from university of Gothenburg, Sweden. He completed neurology residency from university of Toronto (Canada) in 2007 thenfollowed with 2 years fellowship in neu-romuscular diseases from university of Toronto.

Dr. Abubaker was a part of several researches especially on multiple sclerosis, autoimmune dis-eases, Amyotrophic lateral sclerosis (ALS), frontal lobe disease and research on incidence of DVT in ALS.


Faculty Profile

David ElizerAssociate Professor Department of Biochemistry Weill Cornell Medical Col-lege USA

Boulos-Paul BejjaniAssociate Professor of Neurology,Director of the Parkinson’s Disease and Memory Center,Notre Dame de Secours Hospital, Byblos,Lebanon

University of Michigan, Ann Arbor, MI B.S. 1984-87 Computer Science,

University of Michigan, Ann Arbor, MI M.S. 1987-88 Computer Science

Stanford University, Stanford, CA Ph.D. 1988-94 Physics/Biophysics

Scripps Research Institute, La Jolla, CA Post-Doc 1994-99 NMR/Molecular Biology 1994-1999 Postdoctoral Fellow with Dr. Peter E. Wright, Scripps Research Institute

1999-2004 Assistant Professor of Biochemistry, Weill Medical College of Cornell University

2004-present Associate Professor of Biochemistry, Weill Medical College of Cornell University

sel (Prof. Claudia Trenkwalder). She established her own research team and focuses on human body fluid biomarker detection and assay development for improving diagnosis of movement disor-ders.

Brit Mollenhauer established a prospective longitudinal cohort of at enrolment 159 de novo PD sub-jects and 110 matched healthy controls (DeNoPa study) for biomarker studies. She is also member of the executive steering committee of the Parkinson’s Progression Marker Initiative (PPMI) of the Michael J. Fox Foundation.


Glenda HallidayHead, Ageing and Neurodegeneration Department Neuroscience Research AustraliaAustralia

Glenda Halliday is an expert in the pathogenesis of Parkinson’s disease and other neurodegenera-tive disorders. She received her degrees from the University of New South Wales and postdoctoral training at the Centre for Neuroscience, Flinders University of South Australia prior to returning to Sydney as an Australian Research Council Queen Elizabeth II Fellow. She has been a research fellow of the National Health and Medical Research Council of Australia since then and one of the senior scientists at Neuroscience Research Australia (joined in 1993). She has published over 400 research articles and two books, the most recent on Parkinson’s disease, and was president of the Australian Neuroscience Society from 2006-2007. Her research has highlighed the broader patho-

Faculty Profile

Faycal HentatiHead of department of Neurology Mongi Ben Hamida National Institute of NeurologyTunisia

Professor Faycal Hentati heads the department of neurology and neurobiology laboratory at the na-tional institute of neurology in Tunis (Tunisia) since 1995 .he is professor of neurology at the faculty of medicine of Tunis since 1990. His training was at faculty of medicine of Tunis (Tunisia), Bicetre and Salpetriere hospitals in Paris (France), and mass general hospital in Boston (USA).

He was involved with his group since more than 25 years in the study of prevalent hereditary neu-rological diseases in Tunisia and contributed to the description of new genetic entities, to the gene identification of numerous hereditary diseases frequent or specifically encountered in Tunisia. Vari-ous national and international agencies such as American muscular dystrophy association (MDA), association française contre les myopathies (AFM), the European commission and the Michael j. Fox foundation (MJFF) for Parkinson’s have funded this research. Professor Faycal Hentati is the author of more than 160 scientific publications, his index is h-index: 39, and g-index: 77 (June 2012). He is member of the editorial board of some scientific journals. He is president of the Tunisian asso-ciation of neurosciences and member numerous scientific associations. He is a TWAS fellow since 2000 and obtained the first biotechnology presidential price (Tunisia) in 2002, “Gaetano conte” price “(Italy) in 2001 and is “chevalier of the order of national merit” since 1998.


Faculty Profile

Hilal A. LashuelSwitzerland

logical involvement in Parkinson’s disease and her pathological work on dementia with Lewy bodies has been incorporated into highly cited research criteria for the diagnosis of this disorder, highlight-ing the association between Lewy body deposition and visual hallucinations rather than a loss of function.

Dr. Hilal A. Lashuel received his B.Sc. degree in chemistry from the City University of New York in 1994 and completed his doctoral studies at Texas A&M University and the Scripps Research Insti-tute in 1999. After obtaining his doctoral degree, he became a research fellow at the Picower Insti-tute for Medical Research in Long Island New York. In 2001, he moved to Harvard Medical School and the Brigham and Women’s Hospital as a research fellow in the Center for Neurologic Diseases and was later promoted to an instructor in neurology at Harvard Medical School. During his tenure (2001-2004) at Harvard Medical School his work focused on understanding the mechanisms of protein misfolding and fibrillogenesis and the role of these processes in the pathogenesis of Par-kinson’s and Alzheimer’s disease. In 2005 Dr. Lashuel joined the Brain Mind Institute at the Ecole Polytechnique Fédérale de Lausanne (EPFL) where he currently directs the laboratory of molecular and chemical biology of neurodegeneration (http://lashuel-lab.epfl.ch).

Research efforts in the Lashuel’s laboratory cover the following topics: (1) Elucidating the structural basis of amyloid-associated toxicity in neurodegenerative diseases, including Alzheimer’s, and Par-kinson’s disease; (2) Developing innovative chemical approaches and novel tools to monitor and control protein folding, self-assembly and post-translational modification in vitro and in vivo; (3) Identifying and validating new therapeutic targets for treating Parkinson’s disease; (4) Developing novel therapeutic strategies to treat neurodegenerative diseases based on modulationof protein aggregation and clearance.


Faculty Profile

Jing ZhangDirector, UW Medicine NeuropathologyShaw Endowed Chair and Professor of PathologyUniversity of Washington School of MedicineUSA

Jing Zhang (MD, PhD), Professor of Pathology and Adjunct Professor of Neurology and Ophthalmol-ogy at the University of Washington (UW) School of Medicine in Seattle, Washington, is the Director of Neuropathology Division of UW Medicine. He is also the holder of Shaw Endowed Chair in Neu-ropathology. Dr. Zhang received his initial undergraduate and medical training in Shanghai, China (Second Military Medical College). After graduating from a PhD program in Cell Biology at Duke University in 1995, he finished his medical residency and fellowship in Anatomic Pathology and Neuropathology, respectively, at Vanderbilt University in 2001. At the same time, he also becomes specialized in ophthalmic pathology. Currently,

Dr. Zhang is a practicing neuropathologist as well as an ocular pathologist in UW Medicine and affiliated hospitals. Besides his clinical duties, Dr. Zhang leads a research team focused on neuro-degenerative disorders, especially Parkinson’s disease and related disorders, including Alzheimer’s disease. He is particularly interested in translational medicine, with biomarker discovery and valida-tion as the major emphasis. To date, most of his work has been concentrated on the biomarkers, e.g. alpha-synuclein, DJ-1, tau and a few inflammatory species, in the cerebrospinal fluids of Parkinson’s patients, along with age-matched controls and those with other neurodegenerative disorders; but recently his team is leading the effort to translate CNS based markers to the peripheral body fluids, including plasma and saliva, which are much more accessible (than CSF) clinically.

Easy access of body fluids is critical to screening biomarkers that, when identified, can substantially assist clinicians in identifying Parkinson’s patients at early stages, thereby effectively increasing therapeutic windows. Dr. Zhang’s research is well funded, with multiple grants from the NIH in addi-tion to several private foundations, e.g. Michael J. Fox Foundation


Faculty Profile

John Hardy Professor of NeuroscienceUniversity College LondonUK

Prof John Hardy is a geneticist and molecular biologist whose research interests focus on neurologi-cal disease. Dr. Hardy received his B.Sc. (Hons) degree from the University of Leeds, UK (1976) and his Ph.D. from Imperial College, London, UK where he studied dopamine and amino acid neu-ropharmacology.

Dr. Hardy received his postdoctoral training at the MRC Neuropathogenesis Unit in Newcastle upon Tyne, UK and then further postdoctoral work at the Swedish Brain Bank in Umeå, Sweden where he started to work on Alzheimer’s disease. He became Assistant Professor of Biochemistry at St. Mary’s Hospital, Imperial College, London in 1985 and initiated genetic studies of Alzheimer’s dis-ease whilst there.

He was appointed Associate Professor in 1989 and then took the Pfeiffer Endowed Chair of Alzhei-mer’s Research at the University of South Florida, in Tampa in 1992. In 1996 he moved to the Mayo Clinic in Jacksonville, Florida, as Consultant and Professor of Neuroscience. He became Chair of Neuroscience in 2000 and moved to NIA as Chief of the Laboratory of Neurogenetics in 2001. He won the MetLife, the Allied Signal and the Potamkin Prize for his work in describing the first genetic mutations, in the amyloid gene in Alzheimer’s disease, in 1991.

He was Head of the Neurogenetics Section, National Institute of Ageing, Bethesda, USA and in 2007 took up the Chair of Molecular Biology of Neurological Disease at the UCL Institute of Neurology.With over 23,000 citations, Prof Hardy is the most cited Alzheimer’s disease researcher in the UK (5th internationally). In recognition of his exceptional contributions to science, he was elected a Fel-low of the Royal Society in 2009.


Faculty Profile

John Q. TrojanowskiCo-Director – CNDR Medicine University of PennsylvaniaUSA

Karina FogHead of Department Neurodegeneration 1 H. Lundbeck A/SDenmark

Dr. John Q. Trojanowski obtained his MD/PhD in 1976 from Tufts, and after training at Harvard and Penn, he joined the Penn faculty in 1981 where he is Professor, and directs the NIA Alzhei-mer’s Center, the NINDS Udall Parkinson’s Center and the Penn Institute on Aging. His research focuses on Alzheimer’s and Parkinson’s disease as well as frontotemporal degeneration (FTD) and amyotophic lateral sclerosis (ALS) or Lou Gehrig’s disease. With his collaborator, Dr. Virginia Lee, he identified major disease proteins in Alzheimer’s, Parkinson’s, FTD and ALS which created new opportunities for drug discovery that he and Dr. Lee pursue at Penn. His research has placed him among the top 5 most highly cited scientists in his field and his research has been recognized by the Metropolitan Life Foundation Award For Alzheimer’s Disease Research (1996), the Potamkin Prize For Research In Pick’s, Alzheimer’s And Related Diseases (1998), the first Pioneer Award from the Alzheimer’s Association (1998-2003), the 2004 Irving Wright Award of Distinction of the American Federation for Aging Research, and the 2012 Pasarow Award. He was elected to the Institute of Medicine in 2002 and led an effort to prepare a PBS film entitled “Alzheimer’s Disease-Facing the Facts” that aired on PBS in 2009-2010 which won an Emmy Award for best documentary film.

Positions/ Education/ Academic degrees:2008 – present: Head of Department, currently Neurodegeneration 1, H. Lundbeck A/S2007-2008 Principal Research Scientist, H. Lundbeck A/S, Denmark2004 PhD in Neurobiology, Department of Pharmacology, The Danish University of Pharmaceutical Sciences, Denmark. 1995 – 2007 Research Scientist, H. Lundbeck A/S1995 M.Sc. in Neurobiology from University of Odense, Denmark.


Faculty Profile

Leonidas StefanisProfessor of Neurology and Neurobiology University of AthensGreece

Research interest and scientific experience:17 years experience in Drug Discovery, particular with focus on establishing cell based models with disease relevant endpoints, target finding screens and target validation.Member of cross-divisional research teams coordinating early project activities within a specific disease area. Chair of the corporate Parkinson’s Disease Team for 5 years (2006-2010) being responcible for initiating research activities within Parkinson’s disease and manage the activities during the early phases (target identification, establishing the initial link to the disease, assay development, HTS screen, early chemistry). Research representative in the corporate Parkinson’s Disease Strategy Group (2006-2010). Project manager of Drug Discovery projects. Spokesman for Lundbeck Research-Parkinson’s Disease. Current focus is identification and validation of novel drug targets and overall management of Drug Discovery projects addressing misfolded proteins in Neurodegenerative Diseases.

Dr. Stefanis obtained his MD from the University of Athens Medical School in 1987. He subsequent-ly obtained his PhD from the same University in 1992, with work related to the molecular basis of thalassemia. In 1991, he moved to the US, where he trained as Resident in Neurology at Columbia University in New York. In 1995, he embarked on a post-doctoral fellowship in the laboratory of Dr. Lloyd Greene, in the Dept. of Pathology, while in parallel he completed a two-year fellowship on Neu-robehaviour, in the Dept. of Neurology at Columbia University. His work during this time centered on mechanisms of neuronal cell death. In 1998 he was appointed Assistant Professor of Neurology in the Center for Neurodegenerative Diseases in the Dept. of Neurology at Columbia University, posi-tion which he held up till 2003. During this time, he focused his interest more on the pathogenesis of neurodegenerative disorders, with an emphasis on Parkinson’s Disease (PD). In 2003 he moved back to Greece as Researcher Level B at the Biomedical Research Foundation of the Academy of Athens (BRFAA), and set up a laboratory focusing on mechanisms of neurodegeneration, in particu-lar in relation to protein degradation systems, alpha-synuclein and PD. Since 2006 he has assumed the appointment of Associate Professor of Neurology and Neurobiology in the University of Athens Medical School, while he continues his work at BRFAA as an affiliated investigator. Currently, Dr. Stefanis is investigating various areas of PD pathogenesis, ranging from the bench to the bedside. He is examining the genetic underpinnings of the disease in the Greek population, not only in the rare familial, but also in sporadic cases. He is involved in studies that aim to examine the utility of using alpha-synuclein as a disease biomarker. He is examining pathways of neurotoxicity induced by aberrant alpha-synuclein, with an emphasis on the involvement of protein degradation pathways, such as Chaperone-Mediated Autophagy. He is also investigating the molecular underpinnings of the link of other genetic alterations linked to PD, such as those in UCH-L1, LRRK2 and GBA.


Faculty Profile

Lisa McConlogueDistinguished Research Fellow Exploratory Research Elan PharmaceuticalsUSA

Lucilla ParnettiAssistant Professor Section of Neurology University of Perugia Italy

Lisa McConlogue is currently a Distinguished Research Fellow at Elan Pharmaceuticals. Her edu-cational training was in mathematics and biophysics at the University of California at Los Ange-les, with postdoctoral training at the University of California at San Francisco in cellular genetics and molecular biology. At Elan, Lisa initially worked on Alzheimer’s disease, developing animal models, elucidating disease mechanisms in cell and animal models, and identifying and validating therapeutic targets including BACE, the rate limiting enzyme in the production of the AD plaque component A-beta.. More recently, Lisa’s focus has changed to Parkinson’s disease and she led the Elan Parkinson’s disease discovery effort to the point that it spawned a number of independent projects including synuclein modification, synuclein vaccine based approaches and development of pharmacological chaperones for alpha- synuclein.

Education:1981: Medical Degree, Perugia University1984: Post-Graduate Degree in Gerontology and Geriatrics, Florence University1988: PhD, Modena University2002: Post-Graduate Degree in Neurology, Perugia UniversityScholarships and Research Experience Abroad:1983: internship on clinical and neuropsychological aspects in psychogeriatrics at Brighton Clinic, Newcastle upon Tyne, UK, under the guidance of Dr. G. Blessed. 1984: internship on neurophar-macology at the National lnstitute of Aging-National lnstitute on Drug Abuse, Baltimore, MD, under the guidance of Dr. E.D. London. 1985-’86: research fellow in the Department of Psychiatry and Neurochemistry, Goteborg University, S, under the guidance of Proff. L. Svennerholm (Neurochem-istry Section) and C.G. Gottfries (Psychiatry Section), as responsible for a research project on CSF markers in Alzheimers Disease.


Faculty Profile

Maria Grazia SpillantiniProfessor of Molecular Neurology Clinical Neurosciences University of CambridgeUK

Positions Held:1983-1997: responsible of the Aging Brain Research Center, Section of Gerontology and Geriatrics, Perugia University; 1990-1997: assistant professor in Gerontology; sìnce 1997: docent of Neurol-ogy, Perugia University; responsible for the Stroke Unit from 1997 to 2003. At present: responsible for the Memory Clinic, Alzheimer Center, University of Perugia. From 2010 leader and coordinator for the Italian Neurological Society of clinical neurological Italian centres active in CSF analysis in neurodegenerative disorders

Topics of Interest:Clinical, neuroimaging and biological features of degenerative dementias; biomarkers of Alzheimer’s disease and parkinsonisms; pharmacokinetic and pharmacodynamic characteristics of cerebroac-tive drugs; early diagnosis and pharmacological strategies for Parkinson’s disease.

Scientific Publications and Activity:Over 250 scientific papers (164 in international peer reviewed journals) in the fields mentioned above. lnvited speaker in several intemational congresses, including teaching courses on dementia disorders, stroke, Parkinson’s disease. Reviewer of the journals Science, Lancet Neurology, Brain, Neurology, JNNP, Stroke, Neurosci. Lett., Brain Res., Arch. Gen. Psychiatry, Biol. Psychiatry, JAD, J Neurol Sci, Acta Neurol Scand, Aging-Clin&Exp.Res., Drugs, Drugs & Aging, Pharmacoeconomics, CNS Drugs.

Maria Grazia Spillantini is Professor of Molecular Neurology at the Clinical School of the University of Cambridge, UK. She was born in Arezzo, Italy. After receiving a Laurea in Biological Sciences, summa cum Laude, in 1981 from the University of Florence, Italy, she pursued research at the De-partment of Clinical Pharmacology of the University of Florence, at the Unité de Neurobiologie of the INSERM in Paris and at the Molecular Neurobiology Unit of the Medical Research Council in Cambridge. In 1987 she moved to the Medical Research Council Laboratory of Molecular Biology, where first, working in Dr Michel Goedert’s group, she obtained a Ph.D. in Molecular Biology from Cambridge University (Peterhouse) and later she worked as postdoctoral fellow with Prof. Sir Aaron Klug. Following a brief period as tenured scientific staff at the Institute of Cell Biology of the Ital-ian National Research Council in Rome she moved to the Brain Repair Centre of the University of Cambridge at the Department of Clinical Neurosciences where she is at present. Her group works on the molecular neuropathology of diseases characterised by tau and alpha-synuclein aggregates. She identified with her collaboratores alpha-synuclein as the major component of the filaments that form the Lewy bodies in Parkinson’s disease and dementia with Lewy bodies and described one of the first mutations in the Tau gene leading to Frontotemporal dementia and Parkinsonism linked to chromosome 17. She is Fellow of the Academy of Medical Sciences, London; and official fellow of Clare Hall and life member of Peterhouse, Cambridge.


Faculty Profile

Matt FarrerProf of Medical Genetics Canada Excellence Research Chair Medican Genetics University of British Columbia Canada

Michael LeeProfessor Neuroscience University of MinnesotaUSA

Matt Farrer PhD is a Professor of Medical Genetics at UBC, and formerly a Professor of Molecular Neuroscience at Mayo Foundation. He has a background in biochemistry, human genetics and neu-roscience. He currently holds an inaugural Canada Excellence Research Chair in Neurogenetics and Translational Neuroscience and a British Columbia Leadership Chair in Genetic Medicine. He serves on the Scientific Advisory Board of Parkinson’s Society Canada and the Executive Scientific Advisory Board of the Michael J Fox Foundation (MJFF). Matt Farrer recently founded/directs the Centre for Applied Neurogenetics (CAN: www.can.ubc.ca), affiliated with the Brain Research Cen-tre at the University of British Columbia, Vancouver, Canada. CAN’s research is disease-oriented, to discover susceptibility underlying neurodegeneration through human genetics, and to apply that knowledge to model creation/characterization for translational neuroscience. Matt Farrer has co-authored >250 articles on parkinsonism and related disorders; seminal discoveries include rare mutations/polymorphic variability in alpha-synuclein and leucine-rich repeat kinase 2, both major contributors to disease risk.

Dr. Lee is Professor of Neuroscience and Co-director of Center for Neurodegenerative Diseases, Institute for Translational Neuroscience at University of Minnesota. Prior to arriving at University of Minnesota, Dr. Lee was faculty at Department of Pathology, Johns Hopkins University. Dr. Lee’s laboratory is involved in the studying of molecular biological mechanisms of neurodegenerative diseases, particularly Alzheimer’s disease (AD) and Parkinson’s disease (PD). In particular, Dr. Lee uses transgenic mice that express mutant genes to model human disease in order study in vivo mechanisms of neurodegeneration associated AD and PD. Such studies are critical for under-standing the pathogenic events associated with AD and PD and devising new therapies for these diseases.


Faculty Profile

Michael G. Schlossmacher, M.D.Bhargava Research Chair in NeurodegenerationProgram in Neuroscience, Ottawa Hospital Research InstituteDivision of Neurology, The Ottawa HospitalUniversity of OttawaCanada

Dr. Michael Schlossmacher is a clinician scientist with a focus on neurodegenerative diseases. In 1987, following completion of medical school in Vienna, Austria, he began graduate studies in hu-man biology. A Fulbright Commission scholarship enabled him to visit Harvard University.

He subsequently pursed post-doctoral work on the molecular pathology of Alzheimer disease in the laboratory of Dr. Dennis J. Selkoe (1988-1992). Following residency training in general medicine in Vienna (1992-1995), Dr. Schlossmacher completed adult neurology training in the Harvard Long-wood Neurology Program (1995-1999) and a clinical fellowship in movement disorders at Brigham & Women’s Hospital and Massachusetts General Hospital (1999-2001). Since 2000, he has focused his research activities on Parkinson disease, initially under the mentorship of Drs. Dennis J. Selkoe, Kenneth S. Kosik and Peter T. Lansbury. In 2003, he became an independent investigator at the Center for Neurologic Diseases at Brigham & Women’s Hospital, and was appointed Assistant Pro-fessor in Neurology at Harvard Medical School in 2004.

Recruited by the Ottawa Hospital Research Institute (OHRI) and University of Ottawa with support from the Canada Research Chair Program, Dr. Schlossmacher moved to Ontario in late 2006. He opened a new laboratory as a member of the Parkinson’s Research Consortium Ottawa in early 2007. In October 2012, he was named the Bhargava Research Chair in Neurodegeneration at the OHRI. The appointment was made possible through the generous support from Mrs. Uttra and Mr. Sam Bhargava and their family.


Faculty Profile

Nadia StefanovaAssociate Professor Department of Neurology Medical University of Innsbruck Austria

Training1988 – 1994 MD, Medical University, Sofia1997 – 1999 PhD Neuroscience, Medical University, Sofia2003 MD, University of Innsbruck2007 Habilitation in Neuroscience, Medical University Innsbruck, Career History1997-2000 Assistant Professor of Anatomy, Histology and Cytology, Medical University, Sofia1999 Visiting Scientist, Neuroregulation Lab, Department of Physiology, Leiden University Medical Center, the Netherlands2001 Visiting Scientist, Section of Neuronal Survival, Wallenberg Neuroscience Center, Lund University, Sweden1999-2006 PostDoc, Department of Neurology, University of Innsbruck, Austria2007-2011 Assistant Professor of Neuroscience, Department of Neurology, Innsbruck Medical University, AustriaSince 2011 Associate Professor of Neuroscience, Department of Neurology, Innsbruck Medical University, AustriaAwards:1999 Fellowship of the Austrian Academic Exchange Program2003 Prise of the Austrian Society of Neurology2004 Prise of the Austrian Society of Neurology2007 Science award from the City of Innsbruck

Review Panels:Journals Ad hoc referee: Neurobiol Dis, J Neurochem, Brain, Neurosci Lett, Mov Disord, Acta Neuropathol, Amino Acids, Parkinsonism& Related Disord, Neurobiol Aging, PloSOne, Sci Rep Nature, Mol Neurodeg, Exp Gerontol, Cell TransplantationGrants Parkinson’s Disease Society of the UK (PDS), Austrian National Bank Jubilee Fund (ÖNB)Publications: Over 50 original peer-reviewed papers 1 Monograph Over 10 book chapters Over 20 invited international lecturesMembership: -Movement Disorders Society -Society for Neuroscience -European MSA Study Group -Network for European Intracerebral Transplantation and Restoration (NECTAR)


Faculty Profile

Omar M. El-AgnafProfessorDepartment of BiochemistryUnited Arab Emirates University, UAE

Born in Libya and educated at Tripoli University, Prof. Omar El-Agnaf received his PhD degree in Biochemistry from The Queen’s University of Belfast, in 1997. After postdoctoral training at The Queen’s University of Belfast and then St. George’s Hospital Medical School, he moved in 2001 to establish his research group at Lancaster University. Since 2009 he holds a position as Professor of Biochemistry at Faculty of Medicine and Health Sciences, UAE University. He has published over 75 peer-reviewed articles, and he serves on the editorial boards of several international journals. Prof. El-Agnaf’s laboratory is actively engaged in developing biomarkers and drugs discovery for neurodegenerative diseases such as Parkinson’s and Alzheimer’s.


Faculty Profile

Pamela McLeanAssociate Professor Dept of Neuroscience Mayo Clinic FloridaUSA

Philipp KahleProfessorHertie Institute for Clinical Brain ResearchTübingen, Germany

Dr Pamela McLean received her Ph.D in Pharmacoogy and Experimenta Therapeutics from Boston University School of Medicine in 1997. Thereafter she joined Massachusetts General Hospital/Har-vard Medical School as a post-doctoral fellow. Dr McLean spent 14 years at Massachusetts General Hospital during which time she rose thought the ranks at Harvard Medical School from postdoctoral fellow to Instructor in 2001 and then to the rank of Assistant Professor in February 2007. During her time at MGH Dr McLean established an internationally recognized laboratory studying vellular mechanisms of Parkinson’s disease. In April of 2012, Dr McLean was recruited to Jacksonville, Florida where she joined the faculty in the Department of Neuroscience at the Mayo Clinic Florida as a Senior Associate Consultant and Associate Professor.

Research in Dr McLean’s lab focuses on understanding the cellular and molecular mechanisms underlying neurodegenration in Parkinson ’s disease, dementia with Lewy bodies and related disor-ders. In particular her research group studies the role of alpha-synuclein, a protein that is thought to be intimately involved in Parkinson’s disease, Lewy body disease and related disorders. Alpha Sy-nuclein accumulates in Lewy bodies in the neurons that are prone to die in these diseases. Further-more, several mutations have been identified in the gene encoding alpha-synuclein that are linked to familial forms of Parkinson’s disease. Dr McLean has published over original, 50 peer-reviewed articles and reviews and her research is currently supported by two NIH RO1 grants. At the Mayo Clinic, Dr McLean’s lab will continue to study the biology of alpha-synuclein using state-of-the art cell based assays, novel imaging techniques and whole animal models.

Academic Education1984-1989 undergraduate student, Natural Sciences at the Swiss Federal Institute of Technology (ETH) Zurich, SwitzerlandApr. 3, 1989 Diploma for research on the promoter interaction of T7 RNA polymerase.1990-1994 graduate student, Natural Sciences at the University of Basel, SwitzerlandJan. 6, 1994 PhD (cum laude) for research on the structure and function of NGF.


Faculty Profile

Poul Henning JensenProfessor Biomedicine Aarhus UniversityDenmark

Poul Henning Jensen is an expert in functions of alpha-synuclein in pathological settings. He re-ceived his M.D. degree at Aarhus University and internship at Aarhus University hospital. His Ph.D. studies and further research training was obtained at the institutes of Physiology and Medical Bio-chemistry, Aarhus University and as visiting scientist at EMBL, Heidelberg, Germany. He served at head of the Institute of Medical Biochemistry from 2002-2011 and is board member of the Danish Society for neuroscience. His main interesting is the study of alpha-synuclein aggregation- and phosphorylation-dependent effects in vitro, in cells and animal models.

Postdoctoral Training

1994-1998 postdoctoral fellow in the Department of Neurobiology, Stanford University School of Medicine, Stanford (CA), U. S. A.

1998-1999 postdoctoral fellow at the Central Institute for Mental Health, University of Heidelberg, Mannheim, Germany

Advanced Professional Degrees

1999-2004 Senior Scientist (C1), Laboratory of Alzheimer’s and Parkinson’s Disease Research, Department of Metabolic Biochemistry Ludwig Maximilians University of Munich, Germany Head, Parkinson’s Disease Research Group

2004 Habilitation „Molecular Biology and Animal Models of Hereditary Parkinson’s Disease Caused by a-Synuclein and DJ-1 Mutations“

2005-2006 Senior Lecturer (C2), Laboratory of Alzheimer’s and Parkinson’s Disease Research, Department of Metabolic Biochemistry Ludwig Maximilians University of Munich, Germany

2006-present Associate Professor with tenure (W3) Laboratory of Functional Neurogenetics, Department of Neurodegeneration Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases Faculty of Medicine, University of Tübingen, Germany


Faculty Profile

Quyen HoangAssistant ProfessorDepartment of Biochemistry and Molecular Biology,Stark Neurosciences Research InstituteIndiana University School of Medicine,USA

Samir AtwehProfessor and Head, Division of NeurologyAmerican University of BeirutLebanon

Dr Hoang is currently an Assistant Professor of Biochemistry at Indiana University Schoo of Medi-cine. He obtained his bachelor degree in Biochemistry (1997) from McMaster University in Canada. He then joined the laboratory of Daniel Yang at the same institute to pursue his PhD thesis, where he determined the 3 dimensional structure of a bone protein called osteocalcin wich is known as natively unfolded protein at the time. After his PhD (2003), he joined MicroStar Biotech where he headed its Structure-based Drug Discovery Unit. After 1.5 years at MicroStar, he decided to return to academics and joined the laboratory of Gregory Petsko and Dagmar Ringe at Brandeis University in Ealtham for Postdoctoral training; where he determined the structure of UCH-L1. While at Brandeis, he started to develop a research program focusing on Parkinson’s disease-associated genes which he took to this independent laboratory at Indiana University. His laboratory is interested in under-standing the structure and function of proteins associated Parkinson’s disease.

Samir F. Atweh MD is the Head of Neurology and Associate Dean for Medical Education at the American University of Beirut (AUB) in Lebanon. He moved to Lebanon in 1983 after serving for four years at the Department of Neurology of the University of Chicago where he was also the Director of Residency Training under the leadership of Barry G.W. Arnason. Prior to joining the University of Chicago as a faculty member he had completed training in Neuro-Pharmacology at Johns Hopkins School of Medicine and his Neurology training at the Massachusetts General Hospital.

At the AUB he established the first Neurology Training Program in Lebanon, which is modeled after its American counterparts. More than 25 neurologists have graduated from the program and some of them are practicing in the USA. In addition to leading the Division of Neurology he also served as the


Seung Jae LeeProfessor Biomedical Science and Technology Konkuk UniversityKorea

Position:2011-present Professor, Department of Biomedical Science and Technology, Konkuk University, Seoul, Korea2006-2011 Associate Professor, Department of Biomedical Science and Technology, Konkuk Uni-versity, Seoul, Korea2000-2006 Assistant Professor, The Parkinson’s Institute, Sunnyvale, CA 1998-2000 Instructor in Neurology, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA1996-1998 Postdoctoral Fellow, Center for Neurologic Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA1995-1996 Postdoctoral Fellow, Laboratory of Molecular Cardiology, NHLBI, NIH, Bethesda, MD

Chair of the Department of Internal Medicine and Associate Dean for Academic Affairs and Medical Education. During his tenure the Division of Neurology saw the establishment of a modern clinical neurophysiology laboratory and an epilepsy/sleep monitoring unit, and a neuron-intensive care unit. A specialized neurology-neurosurgery in-patient unit is scheduled to open early this summer.

Dr. Atweh’s interests are in the fields of Pain, neuro-pharmacology and movement disorders. His research dealt mostly with the pharmacology of opiate receptors and their brain localization. He has also explored spinal and central mechanisms that are involved in the control of pain sensation especially the interactions of multiple sensory systems at spinal and brainstem levels. He also in-vestigated the complex interactions of pain mechanisms with the immune and inflammatory systems that seem to interact, not only in the peripheral tissues, but also centrally in the brain.

Dr. Atweh sees general neurology patients with special interest in patients with pain problems, head-ache and movement disorders. Along with colleagues in neurosurgery he established a service for Deep Brain Stimulation for the treatment of patients with advanced Parkinson ’s disease and Dys-tonia at the AUB.


Suhail AlruknNeurology Consultant Rashid HospitalDubai, UAE

Faculty Profile

Education:1992-1995 PhD Department of Life Science, Pohang University of Science and Technology, Pohang, Korea1990-1992 M.S. Department of Life Science, Pohang University of Science and Technology, Pohang, Korea1985-1989 B.S. Department of Biology Education, Seoul National University, Seoul, Korea

Awards:1995-1997 NIH Postdoctoral Fellowship from Fogarty International Center 2000 International Parkinson’s Research Award (Parkinson’s disease foundation)2010 Excellence in Basic Research (Ministry of Education, Science, and Technology)

Selected Publications1. Bae E-J, Lee H-J, Rockenstein E, Ho D-H, Park E-B, Yang N-Y, Desplats P, Masliah E, and Lee S-J (2012) Antibody-aided clearance of extracellular a-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci. 32, 13454-134692. Bae E-J, Ho D-H, Park E, Jung JW, Cho K, Hong JH, Lee H-J, Kim KP, Lee S-J (2012) Lipid per-oxidation product, 4-hydroxy-2-nonenal, promotes seeding-capable oligomer formation and cell-to-cell transfer of a-synuclein . Antioxidant & Redox Signaling, in press3. Lee S-J, Desplats P, Sigurdson C, Tsigelny I, Masliah E (2010) Cell-Cell Transmission of Non-Prion Protein Aggregates, Nature Review Neurology, 6, 702-7064. Lee H-J, Suk J-E, Patrick C, Bae E-J, Cho J-H, Rho S, Hwang D, Masliah E, Lee S-J (2010) Direct transfer of alpha-synuclein from neuron to astroglia causes inflammatory responses in synu-cleinopathies. J. Biol. Chem. 285, 9262-9272 5. Desplats P*, Lee H-J*, Bae E-J, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee S-J (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc. Nat. Acad. Sci. USA, 106, 13010-13015


Takafumi Hasegawa, M.D., Ph.D.Assistant Professor Department of NeurologyTohoku University School of Medicine Japan

Academic Education1989-1995 Tohoku University School of Medicine1997-2000 Undergraduate student, Department of Biochemistry at the Miyagi Prefectural Cancer Center, Sendai, JapanMar 2000 Diploma for the Medical Science. Dissertation: Molecular Cloning of Mouse Ganglioside Sialidase and Its Increased Expression in Neuro2a Cell Differen-tiation. Advisor: Prof. Taeko Miyagi

Postdoctoral Training2006-2008 Alexander von Humboldt Research Fellow in Department of Neurodegenerative Diseases, The Hertie-Institute for Clinical Brain Research, Tübingen, Germany. Advisor: Prof. Philipp J. KahlePosition and Internship1995-1997 Internship: Tohoku University Hospital and Kohnan Hospital, Sendai, Japan and Yamagata City Hospital, Yamagata, Japan2000-2001 Staff Physician in Neurology, Tohoku University School of Medicine2001-2002 Chief Physician in Neurology, Osaki Municipal Hospital2003-present Assistant Professor, Department of Neurology, Tohoku University School of Medicine


Faculty Profile

Thomas GasserDepartment of Neurodegenerative Diseases Hertie-Institut for Clinical Brain Research and German Center for Neurodegenerative Disease (DZNE)Germany

The clinical neurologist Thomas Gasser, born in 1958, has made significant contributions to the ge-netics of movement disorders, in particular Parkinson’s Disease. He was one of the first in Germany who combined clinical and molecular genetic expertise in order to map and clone new genes, define genotype-phenotype correlations, explore the functional impact of mutated genes and identify the genetic contribution to common complex neurologic disorders.

The contributions of Thomas Gasser to the genetic basis of Parkinson’s disease and dystonias have been published in high ranking journals, including Science and Nature Genetics. These achieve-ments have also been recognized in the international community as demonstrated by invitations to give plenary lectures at international meetings, among them the International Congress on Parkin-son ’s disease in London 1997 and Vancouver 1999, the Annual Meeting of the Movement Disorders Society in Kyoto in 2006 and the World Parkinson Congress in Glasgow, 2010.

His major discoveries were that mutations in the gene for epsilon-sarcoglycan (SGCE) cause my-oclonus-dystonia, an inherited form of generalized dystonia-plus, and that mutations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, cause the most common form of autosomal dominantly inherited Parkinson’s disease.

This publication in NEURON in 2004 has been cited over 600 times. Work on LRRK2 and Parkin-son’s disease has become a major field of research in neurodegeneration. Together with Dr. Andrew Singleton of the NIH, Bethesda, he was responsible for the first successful genome-wide associa-tion study in Parkinson’s disease, establishing the importance of common genetic variability for the etiology of sporadic PD.

The reputation of Thomas Gasser is documented by memberships of several national and inter-national scientific boards. He is in his second term as a member of the German Research Council (Deutsche Forschungsgemeinschaft, DFG) and his second term as a chairman of the scientific is-sues committee of the Movement Disorder Society. He has been a two term chairman of the scien-tist panel of neurogenetics of the European Federation of Neurological Societies and of the working group for neurogenetics of the German Society of Neurology.

Overall Thomas Gasser may have inspired the interests of many intelligent young neurologists for the field of neurogenetics and thereby has contributed to the remarkable development of the field


in recent years. Over the years he has led and coordinated a number of consorted funded research actions, including the first DFG funded clinical research group on neurogenetics in 2002, a national research network on genetics of Parkinson’s disease as implemented in the German National Ge-nome Research Network (NGFN) as well as several European networks in FP6 and FP7 (Eranet Neuron Project FAMPD and integrated project MEFOPA).

In 2010, he was elected chairman of the scientific advisory board of the “Joint Programming on Neurodegenerative diseases, in particular Alzheimer’s disease”, a highly visible EU-funded pilot initiative of 27 member states which has been established to formulate a strategic research agenda (SRA) as a basis to direct coordinated funding of research by European national funding agencies in this important area over the next years.

Virginia LeeDirector – CNDR Medicine University of PennsylvaniaUSA

Dr. Virginia M.-Y. Lee is the John H. Ware 3rd Professor in Alzheimer’s Research in the Depart-ment of Pathology and Laboratory Medicine. She studied music at the Royal Academy of Music in London (1962-1964), obtained an MS in Biochemistry from the University of London (1968), and received her PhD in Biochemistry from the University of California at San Francisco in 1973. Dr. Lee did postdoctoral studies in pharmacology at the Rudolf Magnus Institute at the University of Utrecht in The Netherlands (1973-1974) and in experimental neuropathology at Children’s Hospital Medical Center and Harvard Medical School in Boston (1974-1979) after which she became Associate Sen-ior Research Investigator at Smith-Kline & French, Inc. in Philadelphia from 1979-1980. She joined the faculty of the Department of Pathology and Laboratory Medicine at the Perelman School of Med-icine of the University of Pennsylvania in 1981 where she rose to the rank of Professor in 1989. Dr. Lee completed the Executive MBA program at the Wharton School of the University of Pennsylvania (1982-1984), and obtained her MBA degree in 1984. She is Director-Center for Neurodegenerative Disease Research and Co-director of the Marian S. Ware Alzheimer Drug Discovery Program at the University of Pennsylvania, School of Medicine. Dr. Lee is the recipient of the Metropolitan Life Foundation Award for Medical Research in Alzheimer’s Disease (1991,1996), the Potamkin Prize for Medical Research in Alzheimer’s Disease (1998), the Bristol-Myers Squibb Biomedical Research Grant in Neuroscience Research (2003) and the 24th Annual Robert J. and Claire Pasarow Founda-tion Award in Neuropsychiatry Research (2012). She was elected to the Institute of Medicine, and is on the Board of Scientific Counselors of the National Institute on Aging.

Research focuses on disease proteins that form pathological inclusions in hereditary and sporadic Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders of aging. Her work

Faculty Profile


demonstrated that tau, alpha-synuclein and TDP-43 proteins form unique brain aggregates in neu-rodegenerative diseases and provided critical evidence that aggregation of brain proteins is a com-mon mechanistic theme in diverse neurodegenerative diseases including AD, PD, FTLD, ALS and related disorders. Dr. Lee’s studies implicated the abnormal aggregation of tau, alpha-synuclein and TDP-43 in mechanisms that compromise neuronal viability. Major accomplishments include discovery of tau, alpha-synuclein and TDP-43 as the diseases proteins in AD, PD and ALS/FTD, respectively, elucidating the roles of these proteins in neurodegeneration, pursuing pathological tau as a target for AD and FTD drug discovery, and advancing understanding of the transmission of pathological tau and alpha-synuclein in cell mouse model systems which could explain disease progression in AD and PD. Most importantly, this research has opened up new avenues of research to identify targets for drug discovery to develop better treatments for these disorders. Because of the broad impact of her research, Dr. Lee is among the top 10 most highly cited AD researchers and she has been recognized as ISI Highly Cited Researcher which has placed her among the top 10 most highly cited neuroscientists from 1997 to 2007.

Faculty Profile

Wei-Ping GaiSenior Lecturer, Department of Human PhysiologyFlinders University of South Australia

Dr. Wei-Ping Gai is currently an NHMRC senior research fellow and senior lecturer Flinders Univer-sity Australia. He completed his Bachelor of Medicine in 1982 and Masters degree in Neuroanatomy in 1985 in China, PhD in Neuropathology in 1997 in Flinders University, Australia. His main research interest is in the cellular and molecular pathology of Parkinson’s and related neurodegenerative diseases with especially focus on the protein compositions of neural inclusions isolated from brains of Parkinson’s and related neurodegenerative diseases and how the inclusion proteins link to the known or unknown etiology and pathophysiology of these diseases, and how to explore the linkage for the treatment and prevention of the diseases.


References: 1. STALEVO [prescribing information]. Novartis Pharma AG. Nov 2010.


References: 1. STALEVO [prescribing information]. Novartis Pharma AG. Nov 2010.

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Important note: Before prescribing, please consult full prescribing information. Presentation: Levodopa / carbidopa / entacapone. 50/12.5/200 mg, 75/18.75/200 mg, 100/25/200 mg, 125/31.25/200 mg, 150/37.5/200 mg and 200/50/200 mg film-coated tablets. Indications / Potential uses: Stalevo is in-dicated for the treatment of adult patients with Parkinson’s disease who have motor fluctuations (known as “end-of-dose” or “on-off” symptoms) that are not stabilized on levodopa/dopa decarboxylase (DDC) inhibitor treatment. Dosage and Administration: Each Stalevo tablet must be taken orally as a complete dose. One tablet contains one treatment dose and may therefore only be administered as a whole tablet. Dosage: The optimum daily dosage of Stalevo must be determined for each patient by careful titration. The daily dosage of Stalevo should preferably be optimized using one of the available dosage strengths. Patients should be instructed to always take only one Stalevo tablet per dose administration. Experience with daily doses greater than 200 mg carbidopa is limited. The maximum recommended daily dose of entacapone is 2000 mg. The maximum dose of Stalevo (up to a dose of 150/37.5/200) is therefore 10 tablets per day, which is equivalent to 7 tablets per day of the 200/50/200 dose. Nausea and vomiting are more likely to occur in patients receiving less than 70–100 mg carbidopa per day. Switching patients taking levodopa/DDC inhibitors (carbidopa or benserazide) and Comtan (entacapone) to Stalevo a. Patients being treated with entacapone and with standard release levodopa/carbidopa at dosage strengths compa-rable to those of Stalevo tablets can be directly switched to the corresponding Stalevo tablets. For example, a patient who has been taking one 50/12.5 mg tablet of levodopa/carbidopa with one 200 mg tablet of entacapone four times daily can switch to one 50/12.5/200 mg Stalevo tablet four times daily. b. If patients are being treated with entacapone and levodopa/carbidopa at doses not equivalent to one of the available dosage strengths of Stalevo, the dose of Stalevo should be carefully titrated to achieve optimum clinical efficacy. At the start of treatment, the dose of Stalevo should be adjusted to corre-spond as closely as possible to the total daily dose of levodopa being used at the time of the changeover. c. When starting treatment with Stalevo in pa-tients being treated with entacapone and levodopa/benserazide in a standard release formulation, levodopa/benserazide should be discontinued the previous evening and treatment with Stalevo initiated the next morning. Initially, a dosage of Stalevo should be chosen that provides either the same amount of levodopa, or slightly more (5–10% more). Switching patients not being treated with entacapone to stalevo Initiation of Stalevo – at doses corresponding to the ones already in use in treatment – should be considered in patients with Parkinson’s disease who display motor fluctuations (so-called “end-of-dose” or “on-off” symptoms) that are not stabilized by their current standard-release levodopa/DDC inhibitor. Note If there is no improvement in clinical symptoms after three months, treatment with Stalevo should be discontinued in these patients, bearing in mind the relevant recommendations and precautions. A direct switch from a levodopa/DDC inhibitor to Stalevo is not recommended in patients with dyskinesias who are undergoing treatment with doses of levodopa in excess of 800 mg per day. In such patients it is advisable to start with entacapone as a separate medication, adjusting the levodopa dose if necessary, before switching to Stalevo. Entacapone enhances the effects of levodopa. It may therefore be necessary, particularly in patients with dyskinesia, to reduce the levodopa dosage by 10–30% during the first days or weeks following the start of treatment. The daily dose of levodopa can be reduced by extending the dosing intervals and/or by reducing the dose of levodopa, depending on the clinical condition of the patient. Dosage adjustment during the course of the treatment If more levodopa is required, an increase in the frequency of doses and/or use of an alternative dosage strength should be considered. This should be effected within the framework of the dosage recommendations. If less levodopa is required, the total daily dosage of Stalevo should be lowered either by reducing the frequency of administration, extending the time between doses or using a different dosage strength of Stalevo. If other levodopa products are used concomitantly with Stalevo, the maximum recommended dosages should be adhered to. Termination of Stalevo therapy If treatment with Stalevo (levodopa/carbidopa/entacapone) is discontinued and the patient is switched to levodopa/DDC-inhibitor therapy without entacapone, it is necessary to adjust the doses of the other antiparkinsonian drugs, especially levodopa, to ensure sufficient control of the parkin-sonian symptoms. Dosage in special patient populations Children and adolescents To date, the safety and efficacy of Stalevo have not been studied in patients under 18 years of age. Therefore, this product cannot be recommended for use in patients under 18 years of age. Elderly patients No adjustment in the dosage of Stalevo is required in elderly patients. Renal impairment Renal impairment does not affect the pharmacokinetics of levodopa or carbidopa. Treatment with Stalevo should nevertheless be administered with particular caution in patients with severe renal impairment. Contraindications: Known hypersensitivity to the active substances or to any of the excipients, severe hepatic impairment, narrow-angle glaucoma, pheochromocytoma, concomitant use with a non-selective monoamine oxidase (MAO-A and MAO-B) inhibitor, concomitant use with a selective MAO-A inhibitor and MAO-B inhibitor, a history of Neuroleptic Malignant Syndrome (NMS) and/or non-traumatic rhabdomyolysis. Warnings / Precautions: ♦Not recommended for the treatment of drug-induced extrapyramidal symptoms. ♦Caution is recommended when Stalevo is administered to patients with ischemic heart disease, severe car-diovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease, chronic wide-angle glaucoma, history of peptic ulcer disease, convulsions, myocardial infarction or ventricular arrhythmias, or past or current psychosis, and in the event of general anaesthesia, extended therapy or when discontinuing treatment. ♦Development of mental changes, depression with suicidal tendencies, and other serious antisocial behaviour should be monitored carefully. ♦Follow-up of weight recommended in patients experiencing diarrhoea. Stalevo should be discontinued if prolonged/persistent diar-rhoea is suspected to be related to the drug. ♦General medical evaluation including liver function in case of progressive anorexia, asthenia and weight decrease within a relatively short period of time. ♦Caution in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorp-tion or sucrase-isomaltase insufficiency. ♦Stalevo should not be used during pregnancy, unless the benefits for the mother outweigh the possible risks to the foetus, nor while breast-feeding. ♦Caution when driving or operating machines; patients presenting somnolence and/or sudden sleep onset episodes must refrain from driving and operating machinery. ♦Not recommended in patients under 18 years of age.Interactions: ♦Symptomatic postural hypoten-sion may occur with concomitant treatment of levodopa with antihypertensives. ♦Caution should be exercised when MAO-A inhibitors, tricyclic antidepres-sants or noradrenaline reuptake inhibitors are used concomitantly. ♦Stalevo can be used with selegiline (a selective MAO-B inhibitor) but the daily dose of selegiline should not exceed 10 mg. ♦Stalevo should be carefully observed for loss of therapeutic response when co-administered with dopamine receptor antagonists (e.g. some antipsychotics and antiemetics), phenytoin and papaverine. ♦A control of INR is recommended when Stalevo is initiated for patients receiving warfarin. ♦Stalevo and iron preparations should be taken at least 2 to 3 hours apart. ♦Stalevo absorption may be impaired in patients on high protein diet. Adverse reactions: Haemolytic anaemia, neuroleptic malignant syndrome, rhabdomyolysis, agranulocytosis, hepatitis with mainly choles-tatic features, malignant melanoma, ischaemic heart disease, myocardial infarction, sudden sleep onset episodes, mental changes including paranoid ideation and psychotic episodes, depression with or without suicidal tendencies, dyskinesia, Parkinsonism aggravated, dizziness, dystonia, hyperkinesia, insomnia, hallucinations, confusion, agitation, nightmares, duodenal ulcer, gastrointestinal bleeding, gastrointestinal symptoms (e.g. nausea, vomiting, abdominal pain, constipation, diarrhoea, dry mouth), discolouration of urine, skin, hair, beard and nails, fatigue, increased sweating, fall, colitis, pathologi-cal gambling, increased libido and hypersexuality, angiodema. Packs and prices: Country specific. Legal classification: Country specific.


Abstracts

Over the last few years, a rapidly growing number of genes for monogenic forms of Parkinson’s dis-ease (PD) have been identified. First, point mutations as well as duplications and triplications have been identified in the gene for a-synuclein (SNCA) in rare families. Although these mutations are extremely rare, their discovery was of particular importance because the encoded protein is the ma-jor component of the histologic hallmark of PD, fibrillar protein aggregates called Lewy bodies and Lewy neurites, and therefore is thought to play a pivotal role in the molecular pathogenesis of the diseases. Later, mutations in the gene for LRRK2 have been discovered to be a much more com-mon cause of autosomal-dominant PD, also with predominant Lewy pathology, while mutations in several other genes have been linked to recessive early-onset variants of PD: parkin, DJ-1, PINK1. All of these genes implicate various cellular subsystems in PD pathogenesis, such as the proteaso-mal protein degradation pathways, protection against oxidative stress and mitochondrial function.Evidence is emerging that low penetrance variants in at least some of these but also several other genes determine the risk to develop the much more common sporadic form of PD. In addition, rare variants with moderate effect size in some other genes, such as the Gaucher’s disease associated gene for glucocerebrosidase A (GBA), also significantly influence the disease risk in a subset of patients.

Thus, an increasingly complex network of genes is emerging, all contributing in different combina-tions with different effect strengths and through different mechanisms to disease risk and progres-sion. These findings provide the “genetic entry points” to identify molecular targets and readouts necessary to design rational disease-modifying treatments.

The pathological diagnosis of idiopathic Parkinson’s disease requires two features; the loss of the pigmented dopaminergic neurons in the substantia nigra and “Lewy body” inclusions in remaining brainstem pigmented neurons. While Lewy bodies were first described by Lewy in 1912, the main protein contained in Lewy bodies was identified as a-synuclein in 1997 following the identification that mutations in the a-synuclein gene was a cause of familial Parkinson’s disease. a-synuclein is one of three soluble synuclein proteins and mutations in all three synucleins cause disease (a-

Where we are with Genetics in Parkinson’s Disease

Pre-Conference WorkshopFriday - 1st March 2013

Neuropathology of Parkinson’s Disease and Related Disorders

Thomas GasserDepartment of Neurodegenerative Diseases Hertie-Institut for Clinical Brain Research and German Center for Neurodegenerative Disease (DZNE)Germany

Glenda HallidayHead, Ageing and Neurodegeneration Department Neuroscience Research AustraliaAustralia


Abstracts

synuclein – Parkinson’s disease, β-synuclein – dementia with Lewy bodies, γ-synuclein – breast cancer), however only a-synuclein has the ability to self-aggregate and form certain inclusions. There are three main types of Lewy body diseases; Parkinson’s disease, Parkinson’s disease with dementia and dementia with Lewy bodies. The main clinical differences between these Lewy body diseases is the timing of symptom onset and dementia severity, and the rate of disease progression, while the main pathological differences are the amount of a-synuclein and Alzheimer-type patholo-gies and the degree and spread of neurodegeneration. a-synuclein also abnormally aggregates in multiple system atrophy, a syndrome commonly misdiagnosed as Parkinson’s disease. In multiple system atrophy, a-synuclein inclusions form in oligodendroglia (called glial cytoplasmic inclusions) instead of neurons, with considerably more a-synuclein in affected brain regions. As for dementia with Lewy bodies, both the rate and spread of degeneration is greater in multiple system atrophy compared with Parkinson’s disease. Pathological aggregates of a-synuclein occur in disorders with different clinical, genetic and pathological features. Understanding this complexity is necessary for diagnostic and treatment developments for these disorders.

Parkinson’s disease (PD) is a common neurodegenerative syndrome with age-related prevalence. Generally PD is considered a sporadic illness but ~14% (range 10-30%) of patients have one or more 1st degree relatives with Parkinsonism. Recent studies have implicated at least 13 PARK loci in disease pathogenesis. In recent years, several monogenetic causes of parkinsonism have been identified including dominant mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2; Lrrk2), and recessive mutations in parkin (PRKN), Pten¬induced kinase 1 (PINK1), DJ-1 (DJ-1) and ATP13A2. We report the results of a prospective clinical, epidemiological and genetic study of Parkinson-ism in Tunisia. This study concerned in total, 1212 structured interviews, clinical examination and blood samples were carried out including 240 patients with idiopathic PD, 91 probands with familial parkinsonism (defined as having one or more affected individuals with 1-3º of blood relationship) and 368 control subjects. Of the 91 probands, 63 kindreds, each containing 2 or more affected in-dividuals, were successfully recruited to include a total of 210 affected and 245 unaffected family members. The 63 kindreds were subsequently genotyped by with 1100 microsatellite markers for linkage analysis.

In familial cases Lrrk2 G2019S mutation was found as the cause of parkinsonism in 34/80 (42%) kindreds including 21homozygous patients.In addition this mutation was found the cause of parkin-sonism in 30% of l patients without known familial history. There were no significant differences in various clinical parameters between LRRK2 and idiopathic PD, although LRRK2 patients seemed to develop less dementia and more motor dyskenesia. The clinical phenotypes in homozygous and heterozygous Lrrk2 G2019S carriers were comparable.Disease penetrance in Lrrk2 G2019S carriers ranges from ~20% in those younger than 50 years to

Role of LRRK2 Gene in Parkinson’s Disease Patient North Africa

Professor Faycal HentatiHead of department of Neurology Mongi Ben Hamida National Institute of NeurologyTunisia


In the recent years increasing attention on biomarkers for neurodegenerative diseases, including Parkinson’s disease (PD), has been paid. The reasons of this growing tendency are several: (i) PD is one of the most common neurodegenerative diseases, affecting approximately 1% of people over 60 years of age. Diagnosis of PD is based on clinical criteria, relying on motor features: rigidity, bradykinesia, resting tremor and in the late stages postural instability. However, clinical diagnosis especially in the early stages of disease can be challenging owing to the difficult differential diag-nosis with essential tremor and atypical parkinsonism, namely multiple system atrophy (MSA), pro-gressive sopranuclear palsy (PSP), and corticobasal degeneration (CBD). Although in movement disorder specialized settings the diagnostic accuracy is satisfactory (≥80%), almost one third of the clinical diagnoses in patients with parkinsonism is revised in the first five years of disease. Diagnos-tic accuracy in the early stages of disease is important, in view of forthcoming disease-modifying therapies. In this perspective, diagnostic biomarkers are urgently needed. (ii) Also, there is the need for progression biomarkers, ie, parameters reflecting a feature associated with disease- severity. (iii) Finally, PD per se is a heterogeneous disease, with different clinical phenotypes (the akinetic-rigid type vs. the tremor dominant variant) and different etiologies (genetic vs. sporadic form), which might have different progression rate, prognosis, thus requiring different therapeutic approaches. Biomarkers are needed in order to reach an early and accurate PD diagnosis, also allowing a dif-ferential diagnosis between PD and other parkinsonism; to differentiate PD with dementia from Alz-heimer’s disease (AD), DLB and other dementias; to differentiate between variants of PD; to monitor disease progression and treatment response. Present data suggest that a combination of different biomarkers reflecting main pathogenic cascades involved in PD represents a promising approach to early diagnosis of this common disabling neurodegenerative disorder.

Clinical use of Biomarkers for Early Diagnosis of PD, Lessons from AD

Lucilla ParnettiAssistant Professor, Section of Neurology University of Perugia Italy

Abstracts

greater than 80% at 80 years .PRKN mutations were rare but homozygous inheritance of PINK1 mutations was found responsible pof PD in d 14% of kindreds with familial parkinsonism. Homozy-gous and compound heterozygous mutations in PRKN and PINK1 are most frequently observed in early-onset Parkinsonism in Asians and Caucasians 58. The most apparent difference between LLRK2 and was the younger age at onset in PINK1 homozygous individuals, with an akinetic-rigid presentation without evidence of subsequent cognitive decline or dementia

Conclusion: Parkinson disease displays a high frequency of genetic forms in Tunisia with in par-ticular a large predominance of Lrrk2 G2019S mutation .This gives an opportunity for a detailed phenotypic analysis and gene penetrance study. Comparative genetic studies in the other Arab and African countries may help the understanding of the causes of this particular distribution of Parkin-sonism in Tunisia


Abstracts

In the presentation “Update on PD: New insight and management”, I shall briefly review some of the critical roadblocks in our understanding of Parkinson disease, in particular as they relate to the pur-suit of developing new therapeutics. The development of drugs that not only provide symptomatic benefits but actually target cause-related, primary events in the development of the disease is long overdue. It is highly probable that some of our currently existing dogmas regarding the etiology of Parkinson disease represent such roadblocks. I will then briefly touch base on the recently pub-lished guidelines by the International Movement Disorder Society with respect to evidence-based guidelines for the treatment of typical Parkinson’s disease.

The symptoms of wearing off are not the same for all parkinson’s patient. In some cases, early wear-ing off is characterized by the return of motor symptoms, such as tremor, rigidity or bradykinesia (slowness of movement). For others, this may also include non-motor symptoms, such as anxiety, fatigue, mood changes, difficulties in thinking, restlessness, sweating or increased salivation.

A physician using a detailed disease history should generally identify wearing off. While many physi-cians recognize wearing off when it is associated with motor symptoms, non-motor symptoms are more difficult to identify. The initial symptoms may be quite minor and may not occur after every dose, or even every day. Physicians and members of the multidisciplinary team is of paramount importance, particularly since symptoms of wearing off may be missed during a routine visit if they are well controlled at the time of consultation.

Increased awareness of the signs and symptoms of wearing off, alongside better recording of these, may help to rectify this and ensure early detection and effective management.

In this presentation Dr. Bejjani is going to speak about the common presentation of the motor and Non-Motor Wearing off phenomena in PD. Also, he will address some useful tools in identifying and assessing Parkinson’s Patients symptoms of wearing off.

Update on PD: New Insight and Management

Motor and Non-Motor Wearing off in Parkinson’s Disease Boulos-Paul BejjaniAssociate Professor of Neurology,Director of the Parkinson’s Disease and Memory Center,Notre Dame de Secours Hospital, Byblos,Lebanon



Abstracts

Parkinson’s disease (PD) is a disabling chronic neurodegenerative disorder clinically character-ized by akinesia, tremor, rigidity, and postural instability, caused mainly by dopaminergic neuron degeneration of the substantia nigra. Levodopa and a number of dopamine agonists are available for a dopamine-replacement therapy resulting in an effective relief of motor symptoms in the early stage of the disease. However, this treatment is eventually hampered by the increasing occurrence of motor complications, such as wearing-off and sudden-off phenomena as well as troublesome hyperkinesias.

Deep brain stimulation (DBS) of the motor thalamus, the ventral intermedius nucleus (VIM), was first used in 1986 to treat medically refractory tremor in PD. DBS of various basal ganglia nuclei has since developed into a highly-effective treatment for several movement disorders. Compared with surgical lesioning procedures, chronic DBS used with the standard stimulation parameters for PD leads to no, or only minimal, tissue damage and is therefore largely reversible. Furthermore, unlike lesioning, bilateral DBS can be implemented without significantly increasing side effects. It is pos-sible to adjust stimulation parameters postoperatively and in the course of the disease.

In this presentation Dr. Atweh is going to speak about the update in DBS in Parkinson’s patients and other movement disorders. Topic will also will cover the challenges with this technology.

Sleep dysfunction is common among patients with Parkinson’s disease and occurs in approximately two thirds of patients. The problems range from noc¬turnal issues such as difficulty with sleep initia-tion, sleep fragmentation, disturbance of circadian rhythm, and rapid eye movement sleep behavior disorder, to daytime problems such as excessive daytime sleepi¬ness.

Frequent nighttime awakening and sleep dis¬ruption are the most common sleep problems in Par-kinson’s disease. Dopamine plays an important role in maintaining wakefulness. To improve sleep in Parkinson’s disease, it is important to achieve the critical balance of adequate dopaminergic therapy and control of symptoms. In this presentation Dr. Alrukn is going to speak about the different mani-festations of Sleep dysfunction in Parkinson’s disease. Also, he will discuss in detail the main etiol-ogy of sleep problems in Parkinson’s dis¬ease and the medications used to treat.

DBS in PD, Still Need Better Management Strategy

Sleep Disorders with Parkinson’s Disease

Samir AtwehLebanon

Suhail AlruknNeurology Consultant, Rashid HospitalDubai, UAE


Abstracts

Early cognitive changes in patients with PD are often subtle and influenced by factors that interact with the disease process, including age of disease onset, medication, and the specific constellation of motor symptoms. These factors notwithstanding, ample evidence exists that specific cognitive changes occur early in the course of PD. This evidence does not imply that cognitive deficits are pervasive during the early stages. To the contrary, they are usually subtle and often difficult to de-tect without formal neuropsychological testing. Depressive symptoms are also common in the early stages of the disease.

In this presentation Dr. Al Madani is going to speak about the early presentation symptoms and signs of cognitive and behavioral changes in PD. Also, he will emphasis the urgency of using a standard tools in identifying these problems.

In the presentation “What to do with patients who have atypical parkinsonism”, I intend to touch base on several atypical parkinsonian disorders that clinicians frequently encounter in their move-ment disorder practice including neurodegenerative and non-neurodegenerative disorders. As time permits, videos of such patients will be shown and their diagnostic workup as well as treatment ap-proaches will be discussed with the audience.

Managing Cognitive and Behavioral Changes in PD

What to do with Patients who have A typical Parkinsonism.

Abu Baker Almadani Neurology Consultant, Rashid HospitalDubai, UAE



Abstracts

Genome-wide association studies (GWAS) have identified a growing number of risk variants for spo-radic PD. Overall, more than 20 loci have been identified and confirmed in at least two studies. The two major risk loci which have been replicated many times are those for alpha-synuclein (SNCA) and the microtubule-associated protein tau (MAPT). Although the functional variants at these loci and the mechanism by which the influence disease risk remains to be precisely determined, there is accumulating evidence that they act primarily by modifying gene expression. eQTL-analyses us-ing genome-wide expression data of post-mortem human brain indicates that this may be a general mode of action of common risk variants. Much more information can be extracted from GWAS than simple one locus associations. For example, the analysis of long stretches of homozygous SNPs (runs of homozygocity, ROH) indicated that additional unknown recessive risk genes are likely to be present in both young and late onset PD. Further analysis of nominally associated variants revealed that some molecular pathways are containing more putatively associated SNPs than others, in par-ticular pathways involved in leukocyte regulation, cytokine signaling and other aspects of immune system function. In addition, GWAS combined with exposure data can contribute to the elucidation of gene environment interactions. GWAS also shed light into associations which have been so far poorly understood, such as the relationship between iron metabolism and PD as well as into some specific features of the disease, such as variability of age at onset or the development of dementia.Nevertheless, even the total risk conferred by all loci found by GWAS combined still explains only a relatively minor fraction of all cases, indicating that GWAS data will have to be combined with whole exome and whole genome sequencing as well with epigenetic and environmental data to fully un-derstand the etiology of PD.

Post-mitotic neurons must maintain exquisite mechanisms to synthesize, recycle, excrete, degrade or sequestrate membrane protein components, whether plasma lemma or mitochondrial. Mutations/subtle flaws may lead to neurodegenerative disease, but as the problem is chronic and progres-sive, rather than acute, effective interventions should be possible. Our challenge is to elucidate the physiologic relationships between these components and most immediately in the context of dopaminergic neurons. To successfully address the problem therapeutically, to develop a disease-

Genetic Modifiers of Sporadic PD: Update on GWAS

New late-onset Autosomal Dominant Genes (EIF4GI & VPS35) – What do they tell us and how do they fit in with AS and LRRK2?

Thomas GasserDepartment of Neurodegenerative Diseases Hertie-Institut for Clinical Brain Research and Ger-man Center for Neurodegenerative Disease (DZNE)Germany

Matt Farrer Prof of Medical Genetics, Canada Excellence Re-search Chair Medican Genetics University of British Columbia Canada

Saturday - 2nd March 2013


Abstracts

modifying (neuroprotective) trial on the basis of the molecular etiology of Parkinson’s disease will require detailed knowledge of the underlying mechanistic biology. Several deleterious mutations now predispose to Parkinson’s disease ‘down the family line’ and many susceptibility variants have been associated. From clinical, genetic and neuroscience perspectives a common theme or synthe-sis is emerging in both: 1) late onset (typical) Lewy body Parkinson’s disease; mutations in genes including alpha-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2), elongation initiation factor 4G1 (EIF4G1), vacuolar sorting protein 35 (VPS) and most recently receptor-mediated endocyto-sis-8 (RME-8), and; 2) early-onset parkinsonism, mutations in genes including parkin (PRKN) and pten-induced kinase 1 (PINK1). The former proteins are often described within the context of ve-sicular/endosomal trafficking and the autophagy-lysosomal system, and the latter are more typically described in terms of mitochondrial maintenance. However, a common denominator appears to be membrane protein recycling/repair, using similar molecular components/machinery within related systems. With a focus on late-onset Lewy body Parkinson’s disease some of the more recent genet-ics and provocative neuroscience will be reviewed.

In Tunisia, 41% of familial and 30% of patients with Parkinson’s disease (PD) may be attributed to a LRRK2 G2019S mutation. Since 2009, clinical data and blood samples have been recruited from 580 patients; 360 with idiopathic PD, 220 with LRRK2 G2019S (23 homozygotes) with informed consent. Logistic and linear regression was performed for autonomic, cognitive (MMSE, MoCA, and FAB), motor (UPDRS), psychiatric (GDS), sensory (Sniffin sticks) and sleep assessments (Ep-worth). No differences were observed between LRRK2 G2019S hetero- and homozygotes, hence these genotypes were combined. With the exception of cognitive testing, the scales applied were sensitive to dysfunction in motor and non-motor domains. Motor assessment between idiopathic PD and LRRK2 parkinsonism was comparable, although difference in gait has been highlighted by others. Geriatric depression and everyday living assessments (Schwab & England) were informa-tive in discriminating patients with PD from control subjects, but could not discriminate LRRK2 par-kinsonism. However, LRRK2 G2019S had fewer problems with REM sleep disorder (16% vs. 29%, p<0.001) and gastrointestinal dysfunction (0.64 vs. 0.74, p<0.04). The sensory study found LRRK2 parkinsonism had olfactory deficits comparable to idiopathic PD, but function was not impaired in asymptomatic carriers. In the LRRK2 group , cognitive impairment was found comparable to idi-opathic PD ( 32.9% for 30.1% of patients on the MMSE, 68.2% for 74,6 % of patients on FAB and in 71.4% for 66.7 % patients on MoCA (with a threshold score of 26) . However a significant differ-ence was found when the a threshold score of 20 Moca test was used with 37,1% of LRRK2ptients showed cognitive impairment against only 13.9% of idiopathic PD (t<5% ) .The age-associated cumulative incidence (penetrance) of parkinsonism for LRRK2 G2019S carriers was 30% at age 50 increasing to 80% at age 70, with similar estimates from case-control (Kaplan-Meier) and family-based (kin cohort) designs.

LRRK2 and PD in Tunisia

Faycal Hentati Head of department of Neurology Mongi Ben Hamida National Institute of NeurologyTunisia


Abstracts

Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy are archetypal sy-nucleinopathies characterized by alpha-synuclein filamentous inclusion bodies in neurons as Lewy bodies in Parkinson’s disease, dementia with Lewy bodies, or oligodendroglial inclusions (GCIs) multiple system atrophy. Despite the cell types affected, these diseases share many similar abnor-malities at molecular, cellar and neural circuitry levels. Here I will summarize our proteomic and immunohistochemical analyses of protein compositions of Lewy bodies and GCIs isolated from postmortem brains to illustrate the features common and distinct between these synucleinopathesis.

Neuropathological Features of Synucleinopathies

Wei-Ping GaiSenior LecturerFlinders University of South Australia

Parkinson’s disease (PD) is characterized by the presence of Lewy bodies and Lewy neurites, intracellular protein aggregates containing filaments made of alpha-synuclein, a protein involved in PD pathogenesis as is also supported by genetic findings. How alpha-synuclein contributes to PD development remains unclear. We have produced a transgenic mouse model that expresses truncated (1-120) human alpha-synuclein under the control of the tyrosine hydroxylase promoter specifically in dopaminergic neurones. In these transgenic mice alpha-synuclein aggregates into granular and filamentous material. At 3 months of age these transgenic mice show striatal dopamine reduction associated with impaired LTP that is rescued by L-Dopa treatment. The transgenic mice show detectable progressive synaptic alpha-synuclein aggregation associated with redistribution of the SNARE complex from 6 months of age, i tis associated with progressive reduction in dopamine release in the absence of dopaminergic neuron death. Similar alterations are also present in the striatum of PD patients with short disease duration. These data with the finding that dopaminergic terminal loss preceedes dopaminergic neuronal death in PD patients, indicate that PD is a dying back pathology starting at the synapse. Compounds acting on aggregated synaptic alpha-synuclein and able to restore neurotransmitter release could be a treatment for PD.

Synapses are Where it all starts? Evidence from Human & Animal Studies

Maria Gracia Spillanti Professor of Molecular Neurology Clinical Neurosciences University of CambridgeUK


Abstracts

The etiology of Parkinson’s disease (PD) is unknown in most cases. The fact that degenerating neuronal populations in PD exhibit ?-synuclein (?S) abnormalities and mutations in ?S gene cause familial PD indicate that abnormalities are mechanistically linked to pathogenesis of PD and other ?-synucleinopathies. Thus, understanding how ?S causes neurodegeneration may identify thera-peutic targets to slow and/or halt the progression of PD. Because cellular accumulation of misfolded proteins can stress protein homeostatic mechanisms, we examined whether ?S causes endoplasmic reticulem stress response. we show that onset of disease in the transgenic model is coincident with the induction of ER chaperones (e.g., BiP/Grp78) in neurons affected by ?-synucleinopathy. The activation of ER charperones occurred in absence of normal UPR associated activation of phospho-eIF2?/ATF4/CHOP. The increased levels of ER/microsomal ?S in mouse and human brains with ?-synucleinopathy and ?S-dependent sensitization of cells to ER stress indicate that ?S-abnormali-ties may have direct impact on ER function in vivo. Increased levels of ER-associated polyubiquitin and activation of ER stress-associated caspases with ?-synucleinopathy support the view that overt ER dysfunction contributes to neurodegeneration. More important, we show that an anti-ER-stress agent, salubrinal, dramatically delays the onset of neurological disease in the mutant ?S transgenic mouse model. Our data indicate that the accumulation of aggregated interacts with ER to induce chronic ER stress conditions that critically contribute to neurodegeneration in ?-synucleinopathies. Further, attenuating ER stress could be an effective therapeutic strategy for PD and other ?-synucle-inopathies. Supported by NIH grants NS038065, NS0380377, NS055776 and ES017384.

Subsequent Steps to Neurodegeneration - Synapses First & Then What?

Michael Lee Professor Neuroscience University of MinnesotaUSA


Abstracts

a-synuclein (αSYN)is an abundant small protein associated with synaptic vesicles. It is genetically and neuropathologically linked to a spectrum of neurodegenerative diseases including Parkinson’s disease, dementia with Lewy bodies (DLB), and related disorders. In disease, αSYN undergoes complex misfolding and aggregation pathways accompanied by phosphorylation at a distinct site (pS129), eventually leading to the formation of the amyloid-like Lewy pathology. Cognitive im-pairment reminiscent of DLB is recapitulated in several AS transgenic mouse lines. We measured neuronal activity induced gene products in the limbic system of αSYN transgenic mice upon fear conditioning (FC).Induction of the synaptic plasticity marker c-Fos was significantly reduced in the amygdala and hippocampus of (Thy1)-h[A30P] α SYN transgenic mice in an age dependent man-ner. Similarly, the neuronal activity inducible polo-like kinase 2 (Plk2) that can generate pS129 was up-regulated in both brain regions upon FC. Plk2 inductions were also significantly impaired in aged (Thy1)-h[A30P] α SYN transgenic mice, both in the amygdala and hippocampus. Plk2 inductions in the amygdala after FC were paralleled by a small but significant increase in the number of neuronal cell bodies immunopositive for pS129 in young but not aged (Thy1)-h[A30P] α SYN transgenic mice. It is interesting to note that in the basolateral parts of the amygdala engaged in synaptic plasticity, pS129 was predominantly found in nuclei where also Plk2 is localized, suggesting an epigenetic regulatory role of nuclear (phospho ) α SYN. Whereas in the central nucleus of the amygdala, pS129-immunoreactive profiles appeared in neurites, where the alternative pS129 kinase Plk3 is localized. We speculate that nuclear Plk2-mediated pS129 is a physiological process related to epigenetic control of sy naptic plasticity, whereas pathological pS129 in Lewy neurites may be medi-ated by other kinases, such as Plk3. This should be considered when exploiting Plks and pS129 as drug targets. Moreover, we observed in the aged hippocampus a distinct type of apparently unmodi-fied transgenic α SYN profiles resembling synaptic accumulations of “normal” α SYN. Perhaps in the hippocampus, elevation of the synaptic α SYN level is sufficient to derange synaptic functions. Thus, the cognitive decline observed in aged α SYN transgenic mice might be due to impairment of neurotransmission and synaptic plasticity in the limbic system by distinct α SYN species.

The protein alpha- synuclein has been thought to be a natively unfolded protein for the past 20 years. However, two groups (Dennis Selkoe’s and mine) recently reported that alpha- synuclein could also exist as a folded tetramer. In this presentation, I will walk through how my group arrived that conclu-sion and provide updates on what we have done beyond what was presented in our paper.

Where does Ser129 Phosphorylation fit in the path?

AS Tetramers, Function & Dysfunction

Philipp KahleProfessorHertie Institute for Clinical Brain ResearchTübingen, Germany

Quyen Hoang, Ph.DAssistant ProfessorDepartment of Biochemistry and Molecular Biology,Stark Neurosciences Research InstituteIndiana University School of Medicine,USA


Abstracts

Alpha-synuclein is found in the form of amyloid fibrils within the Lewy body deposits characteristic of Parkinson’s disease, and point mutations or duplication/triplication of the alpha-synuclein gene cause familial Parkinsonism. AS has long been considered to be an intrinsically disordered protein based on the behavior of the recombinant purified protein when isolated in solution. More recently, it has been proposed that the predominant form of AS in both eurkaryotic tissues (RBCs etc.) and in bacteria is that of a native tetramer with helical structure. Further, several studies have suggested that N-terminal modifications of AS may mediate tetramet formation. I will review pervious and new evidence suggesting that the predominant form of bacterially expressed AS is that of a disordered monomer. N-terminal acetylation does modify the local secondary structure of AS, but does not induce a tetrameric form in bacteria, and does not appear to significantly enhance aggregation of the free state of the protein.

AS Structure/Function & Dysfunction

David Elizer Associate Professor Department of Biochemistry Weill Cornell Medical CollegeUSA


Abstracts

The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation and spreading of a-synuclein (α-syn), the principal component of the intraneuronal inclusions known as Lewy bodies (LBs) and Lewy neurites (LNs) that characterize Parkinson’s disease (PD) and dementia with LBs (DLB) in brain are poorly understood. We demonstrate that pre-formed fibrils (pffs) generated from recombinant α-syn en-ter cultured primary neurons generated from non-transgenic wildtype mice, promote recruitment of soluble endogenous α-syn into insoluble PD-like LBs and LNs. Accumulation of pathologic α-syn led to selective decreases in synaptic proteins, progressive impairments in neuronal excitability and connectivity, and eventually, neuron death. Moreover, we further show that in young asymptomatic α-syn transgenic (Tg) mice, intracerebral injections of synthetic α-syn pffs accelerate both the forma-tion of intracellular LB/LN-like inclusions and the onset of neurological symptoms in recipient ani-mals. Pathologic α-syn propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and dramatically reduced survival with a highly reproducible interval from injection to death in inoculated animals. Thus, synthetic α-Syn pffs are wholly sufficient to initiate PD-like LBs/LNs and to transmit disease in primary neurons in vitro and Tg mice in vivo. Thus, these data support a prion-like cascade in synucleinopathies whereby cell-to-cell transmission and propa-gation of misfolded α-syn underlie the CNS proliferation of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics.

A better understanding of the molecular and cellular determinants that influence the pathology of Parkinson’s disease (PD) is essential for developing effective diagnostic, preventative and therapeu-tic strategies to treat this devastating disease. Evidence from genetics, pathology, animal modelling, cell culture and in vitro biochemical and biophysical studies supports the hypothesis that a-synuclein (α-syn) plays a central role in the pathogenesis of PD and several other neurodegenerative dis-eases, collectively referred to as ‘synucleinopathies’. In PD, several post-translational modifications of a-synuclein are associated with the formation of Lewy bodies in the brains of affected patients of PD and other synucleinopathies. However, whether disease-associated α-syn post-translational modifications promote or inhibit α-syn aggregation and neurotoxicity in vivo remains unknown. To answer this question, we have applied a combination of in vivo modeling, molecular biology, protein engineering, as well as chemical and semisynthetic approaches to introduce and examine the effect of site specific modifications on the structure, aggregation, membrane binding, subcellular localiza-

AS Aggregates/Seeds (Fragments, Function & Dysfunction)

AS Phosphorylation, Function and Dysfunction

Virginia Lee Director – CNDR Medicine University of PennsylvaniaUSA

Hilal LashuelAssociate Professor Brain Mind InstituteÉcole Polytechnique Fédérale de LausanneSwitzerland


Abstracts

tion and toxicity of α-syn in vitro and in animal models of PD. In this talk, I will summarize our latest studies aimed at elucidating the role of disease-associated phosphorylation (at S87, S129, Y125) in regulating the structure, aggregation, subcellular localization and toxicity using cellular and animal models of PD. The results from these studies have led to the identification of novel therapeutic tar-gets and development of mechanistic models that are currently being tested in cellular and animal models of Parkinson’s disease and synucleinopathies.

While the free state of AS is highly disordered, upon binding to membranes, AS can assume several more ordered conformations in which the N-terminal ~100-residue lipid-binding domain of the pro-tein becomes partly or fully helical. We postulate that the fully helical extended-helix form of the pro-tein acts as a reservoir on the synaptic vesicle surface, from which AS molecules can be recruited into the broken-helix form upon the docking of vesicles to the plasma membrane. The membrane-spanning broken helix form can provide stability to the docked vesicles, and may also interact, di-rectly or indirectly, with the SNARE fusion machinery to modulate the efficiency of SNARE-mediate vesicle exocytosis. Furthermore, we have observed partly helical membrane-bound forms of AS which may a play an important role in membrane-mediated aggregation of the protein.

Alpha-synuclein protein levels are considered as a major determinant of its neurotoxic potential, whereas secreted extracellular alpha-synuclein has emerged as an additional important factor in this regard. However, the manner of alpha-synuclein degradation in neurons remains contentious. Both the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP)-mainly macroautophagy and Chaperone-Mediated Autophagy (CMA)- have been suggested to contribute to alpha-synuclein turnover. Additionally, other proteases such as calpains, neurosin and metallo-proteinases have been also proposed to have a role in intracellular and extracellular alpha-synuclein processing. Both UPS and ALP activity decline with aging, and such decline may play a pivotal role in many neurodegenerative conditions. Alterations in these major proteolytic pathways may result in alpha-synuclein accumulation due to impaired clearance. Conversely, increased alpha-synuclein protein burden promotes the generation of aberrant species that may impair further UPS or ALP function, generating thus a bidirectional positive feedback loop leading to neuronal death. In par-ticular with regards to autophagy, data from our lab and others indicates that it is a major avenue for alpha-synuclein degradation in neuronal cells. We have focused in particular on CMA, and

Vesicle Selectivity: Membrane Sensing & Dynamics

Catabolism Through Autophagy

David Elizer Associate Professor Department of Biochemistry Weill Cornell Medical CollegeUSA

Leonidas Stefanis Professor of Neurology and Neurobiology University of AthensGreece


Abstracts

have previously shown that a decrease of the levels of Lamp-2a, the rate-limiting step in this pro-cess, leads to an accumulation of alpha-synuclein in primary neuronal cultures, including ventral midbran dopaminergic neurons; furthermore, alpha-synuclein neurotoxicity is in part mediated via CMA dysfunction (Vogiatzi et al., 2008; Xilouri et al., 2009). We have recently extended this work, using another approach: Lamp-2a overexpression in human neuroblastoma SH-SY5Y cells, rat pri-mary cortical neurons in vitro, and nigral dopaminergic neurons in vivo. Lamp2a overexpression in cellular systems led to upregulation of CMA, decreased alpha-synuclein turnover, and selective protection against adenoviral-mediated WT alpha-synuclein neurotoxicity. Protection was observed even when the steady-state levels of alpha-synuclein were unchanged, suggesting that it occurred through the attenuation of alpha-synuclein -mediated CMA dysfunction. Lamp2a overexpression via the nigral injection of recombinant adeno-associated virus vectors effectively ameliorated alpha-sy-nuclein -induced dopaminergic neurodegeneration by increasing the survival of neurons located in the substantia nigra as well as striatal axon terminals, which was associated with a reduction in total alpha-synuclein levels and related aberrant species. We conclude that CMA induction may provide a novel therapeutic strategy in PD and related synucleinopathies through two different mechanisms: amelioration of CMA dysfunction and lowering of alpha-synuclein levels.

Increased intracellular levels of alpha-synuclein are implicated in Parkinson’s disease and related disorders and may be caused by alterations in the ubiquitin–proteasome system (UPS) or the au-tophagy–lysosomal pathway (ALP). A critical question remains how alpha-synuclein is degraded by neurons in vivo. To address this, our study uses alpha-synuclein transgenic mice, expressing human alpha-synuclein or alpha-synucleinGFP under the (h)PDGF-beta promoter, in combination with in vivo pharmacologic and multiphoton imaging strategies to systematically test degradation pathways in the living mouse brain. We demonstrate that the UPS is the main degradation pathway for alpha-synuclein under normal conditions in vivo while with increased alpha-synuclein burden the ALPis recruited. Moreover, we report alterations of the UPS in alpha-synuclein transgenic mice and age dependence to the role of the UPS in alpha-synuclein degradation. In addition, we provide evidence that the UPS and ALP might be functionally connected such that impairment of one can upregulate the other. These results provide a novel link between the UPS, the ALP, and alpha-synuclein pathol-ogy and may have important implications for future therapeutics targeting degradation pathways.

Proteosome Role in Catabolism Pamela McLean Associate Professor Dept of Neuroscience Mayo Clinic FloridaUSA


Abstracts

After the discovery of alpha-synuclein (αSYN)-positive Lewy body-like inclusions in the grafted neu-rons of Parkinson’s disease (PD) patients who had received transplants of fetal mesencephalic neurons, increasing evidence suggests that misfolded proteins in neurodegenerative diseases can spread from cell-to-cell and encourage the propagation of neurodegeneration in a prion-like manner. It is known that both normal and abnormally folded pathogenic prion proteins were associated with extracellular nanovesicles called ‘exosome’. Thus, it is tempting to speculate that similar mecha-nisms could be involved in the transmission of other amyloidogenic proteins. Recent studies has demonstrated that part of the cell-produced αSYN is secreted via an exosomal, calcium-depend-ent mechanism and that the exosome-containing conditioned medium from αSYN-expressing cells caused the cell death of recipient neuronal cells. However, it has not yet been determined whether αSYN is enriched in exosomes derived from body fluid such as blood, lymph and cerebrospinal fluid (CSF). As reported previously, we found a striking condensation of prion in exosomes in neuronal culture medium and CSF, whereas such enrichment was not observed with αSYN. The marked discrepancy in terms of the exosomal localization implies that the secretory mechanism of αSYN might be different from that of prion protein. This idea is also supported by our findings showing that, in contrast to prion protein, impaired biogenesis of multivesicular body (MVB), an organelle from which exosomes are derived, by dominant-negative (DN) mutant vacuolar protein sorting 4 (VPS4) not only interfered with lysosomal targeting of αSYN but facilitated αSYN secretion. Furthermore, we showed that the functional disruption of recycling endosome by DN-Rab11a decreases of the extracellular oligomeric αSYN in culture medium as well as the accumulation of SDS-resistant αSYN oligomers in the endosome and lysosomal compartments.

The hypersecretion of αSYN in VPS4-defective cells was efficiently restored by the co-expression of DN-Rab11a. These findings indicated that a part of endogenous αSYN was trafficked via a recycling endosome pathway for extracellular secretion, and if the intracellular αSYN reaches a toxic level or the MVB sorting pathway is dammed up for any reason, a torrent of endocytic αSYN may flow out through the recycling endosome pathway. Although the concept of prion-like propagation has been recognized as a common phenomenon in many neurodegenerative diseases, it is likely that the molecular mechanisms underlying the spreading of protein-misfolding may differ depending on the biochemical nature of the protein aggregate, level of cellular stress, or the cell-type. Further studies will be needed to gain insight into the cellular mechanisms of disease progression and to identify molecular targets for therapeutic intervention in PD and other neurodegenerative diseases.

Regulation of AS Secretion

Takafumi Hasegawa, M.D., Ph.D.Assistant Professor Department of Neurology,Tohoku University School of Medicine, Japan


Abstracts

Sunday - 3rd March 2013

a-synuclein opathies are group of neurodegenerative diseases including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), linked to the accumulation of a-synuclein in the brain. Since we reported the presence of a-synuclein in human CSF and blood plasma, several studies have attempted to explore the potential use of a-synuclein as biomarker for PD and related disorders. However, they provided inconclusive and contradictory results. This could be due to the differences in the assays and procedures employed by different laboratories, including handling and storing the CSF samples, and the use of different antibodies employed in the ELISA assays, which rule out the possibility of directly comparing the results obtained. In this seminar I will review the progress which has been made so far and highlights the challenges that lie ahead.

Biomarkers indicative of Parkinson’s traits and states are urgently needed. Currently, the most wide-ly tested Parkinson’s biomarkers, e.g. alpha-synuclein and DJ-1, are all based on the cerebrospinal fluid (CSF), which is in direct contact with the brain and spinal cord, i.e. it reflects brain pathology more directly than other body fluids. However, to effectively diagnose Parkinson’s disease early and monitor its progression more readily, a body fluid more accessible than CSF is needed. Unfor-tunately, most discovery work in plasma or serum for PD (and Alzheimer’s disease for that matter), especially those related to proteins, has achieved very limited success, largely because of enor-mous complexity of blood protein contents and variable matrix effects that result in prominent false positive or negative results. In this presentation, several CSF based markers will be summarized first, followed by discussions on how CSF based markers can be translated to peripheral body fluids, including plasma and saliva. While plasma or serum-based markers have been extensively discussed by others previously, the approach presented here is different in that biomarker discovery in blood will be focused on those derived from the central nervous system (CNS) or CSF. Discovery and validation of potential salivary biomarkers, including alpha-synuclein and DJ-1 as well as their isoforms, are still in its infancy; but in the presentation, promising results will be shown. This line of research is motivated by the observations that several recent investigations indicated that subman-dibular gland is damaged in Parkinson’s patients, with synucleinopathy, sometime even in the cases where no apparent motor symptoms are shown clinically. It is expected that blood and or salivary biomarkers will facilitate the processes of diagnosing PD early, monitoring PD progression and as-sessing PD therapy more objectively.

CSF alpha-synuclein in neurodegenerative disorders: an overview

Parkinson’s Biomarkers - Transition from CSF to Peripheral Body Fluids

Omar M. El-AgnafProfessorDepartment of BiochemistryUnited Arab Emirates University UAE

Jing Zhang MD, PhDDirector, UW Medicine NeuropathologyShaw Endowed Chair and Professor of PathologyUniversity of Washington School of MedicineUSA


Abstracts

Many fundamental decisions in clinical routine are based on biomarkers, but no widely applicable marker is available for Parkinson’s disease and related disorders with three major problems: (1) our diagnosis based on the UK Brain bank Criteria is too late, when more than 50% of dopaminergic neurons are already degenerated; (2) the diagnosis PD is wrong in 10-20% even when diagnosed by movement disorder experts and (3) upcoming neuropreventive treatments may fail, due to the lack of an objective progression marker. The presence of total alpha-synuclein in cerebrospinal fluid (CSF) has long been debated, but has been proven in 2008 by mass spectrometry (Mollenhauer et al., 2008). Several assays for the quantification of total alpha-synuclein in CSF showed a decrease in alpha-synuclein-related disorders: Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) (Tokuda et al., 2006; Mollenhauer et al., 2011; Hong et al., 2010). The decrease could recently also been found in drug-naïve PD cases versus healthy controls (Mollenhauer et al., 2013). And we have shown that CSF alpha-synuclein is derived from neurons of the central nervous system (Mollenhauer et al., 2012).

Between 2009 and 2011 we established a single-center study on 159 at enrolment drug-naïve PD subjects and 110 healthy controls (DeNoPa study), that will be followed biannually for 10-15 years including polysomnography, smell testing, MRI, transcranial ultrasound, CSF, blood sampling, neu-ropsychological testing and questionnaires on non-motor symptoms. Samples will be used for bio-marker validation and to explore new biomarkers by mass-spectrometry including other biological fluids (e.g. urine, saliva). In parallel we established a new multiplex on an electrochemiluminescence platform (Mesoscale Discovery) to quantify total alpha-synuclein, total tau protein, β-amyloid (1-42) and DJ-1 with a single measurement in a single CSF sample of 50 ul.

Biomarkers for the early diagnosis of Parkinson Disease (PD) and to map PD progression as well as to monitor target engagement for disease modifying therapies would accelerate the pace of research to elucidate mechanism of PD and discover effective therapies. Despite progress to iden-tify and validate PD biomarkers, no fully validated biomarker for PD is available while advances in molecular genetics, neurobiology and imaging technologies for PD have been remarkable. Hence, the lack of PD biomarkers is a significant roadblock for further studies of PD mechanisms and for discovery of disease modifying therapies. For these reasons, a major initiative to develop PD bio-markers is urgently needed, and this has lead to the launch of the Parkinson Progression Marker Ini-tiative (PPMI). This is a remarkable public-private consortium to establish a collaborative effort of PD researchers with expertise in biomarker development, PD clinical study design and implementation,

Introduction on total alpha-synuclein in cerebrospinal fluid and what has been achieved

MJFF Parkinson’s Progression Markers Initiative

Brit Mollenhauer Assistant Paracelsus Elena-Klinik Germany

John Trojanowski Co-Director – CNDR Medicine University of PennsylvaniaUSA


Abstracts

Biomarkers for the early diagnosis of Parkinson Disease (PD) and to map PD progression as well as to monitor target engagement for disease modifying therapies would accelerate the pace of research to elucidate mechanism of PD and discover effective therapies. Despite progress to iden-tify and validate PD biomarkers, no fully validated biomarker for PD is available while advances in molecular genetics, neurobiology and imaging technologies for PD have been remarkable. Hence, the lack of PD biomarkers is a significant roadblock for further studies of PD mechanisms and for discovery of disease modifying therapies. For these reasons, a major initiative to develop PD bio-markers is urgently needed, and this has lead to the launch of the Parkinson Progression Marker Ini-tiative (PPMI). This is a remarkable public-private consortium to establish a collaborative effort of PD researchers with expertise in biomarker development, PD clinical study design and implementation, bioinformatics, statistics, and data management that is designed to identify and validate PD progres-sion markers. PPMI is largely sponsored by the Michael J Fox foundation with substantial industry partnerships. PPMI is a five-year observational, international, multi-center study designed to identify PD progression biomarkers both to improve understanding of disease etiology and course and to provide crucial tools to enhance the likelihood of success of PD disease modifying therapeutic trials. The specific goals of PPMI are to: 1) Establish standardized protocols for acquisition, transfer and analysis of clinical, imaging and biospecimen data that can be used by the PD research community; 2) Investigate existing and identify novel clinical, imaging and chemical biomarkers that serve as PD diagnostic and progression markers that individually or in combination will rapidly demonstrate inter-val change in PD patients in comparison to healthy controls or in sub-sets of PD patients defined by baseline assessments, progression milestones and/or rate of clinical, imaging or biosample change; 3) Optimize bioassays and conduct preliminary verification studies on promising biological markers using stored biospecimens. PPMI was planned during a two-year period in a series of workshops with input from academic PD experts, Michael J Fox Foundation scientific staff, and government and industry partners. The study was launched in June 2010 and enrollment is nearly complete. This presentation provides an overview of the overall study design and key study features as well as the organizational structure of PPMI and some of the initial findings to date.Supported by the by the Michael J. Fox Foundation.

Misfolding and aggregation of a-synuclein has been implicated in the pathogenesis of Lewy body diseases (LBD), such as Parkinson’s disease (PD). However, identity of pathogenic forms of this protein and their modes of action remain elusive. Recent studies discovered that a small amount of a-synuclein , albeit a cytosolic protein, is released from neuronal cells via unconventional exocyto-sis, and actions of neuron-released, extracellular a-synuclein account for all the major pathological characteristics found in LBD, such as neurodegeneration, progressive spreading of a-synuclein pa-thology, and neuroinflammation. In this talk, I will critically review my recent work along with a body of rapidly increasing literature proposing extracellular a-synuclein as a novel therapeutic target of LBD and suggest approaches to interfere with its actions to halt the progression of the disease.

Extracellular ASSeung Jae Lee Professor Biomedical Science and Technology Konkuk UniversityKorea


Abstracts

Glia are traditionally know as support cells for neurons and their role in neurodgeneration has been largely considered secondary to neuronal dysfunction. The present study aims to assess reactive changes in different types of astrocytes in Parkinson’s disease (PD), assessing these changes at the time of disease initiation when a-synuclein is accumulating in brain tissue but there is limited neuronal loss, and also as the disease progresses and neuronal loss is evident. Of the two main types of astrocytes, only protoplasmic astrocytes are involved in PD, where they become non-reactive and accumulate a-synuclein . Experimental evidence has shown that astrocytic a-synuclein deposition initiates the non-cell autonomous killing of neurons through microglial signaling. As the disease progresses, more protoplasmic astrocytes are affected by the disease with an increasing microglial response. Glia seem to be responsible for the progression of PD and play an important role in initiating the early tissue response. In particular, early dysfunction and a-synuclein accu-mulation in astrocytes causes recruitment of phagocytic microglia that attack selected neurons in restricted brain regions causing the clinical symptoms of PD.

AstrocytesGlenda Halliday Head, Ageing and Neurodegeneration Department Neuroscience Research AustraliaAustralia

Oligodendrocytes display a heterogeneous population of glial cells with various morphologies, states of maturation and of functional activity. Oligodendroglia can be classified in myelinating cells espe-cially located in the white matter and non-myelinating cells located in the grey matter and around non-myelinated axons. All of them originate from oligodendrocyte progenitor cells (OPCs). The ma-jor function of oligodendroglia is the formation, maintenance and restoration of myelin sheaths. Fur-thermore, oligodendrocytes play an important role in the development, maintenance, neurotrophic support and regeneration of axons, related to the support of neuronal survival.

While oligodendroglial pathology does not seem to be leading in Parkinson’s disease and dementia with Lewy bodies, oligodendrocytes have a significant role in the pathogenesis of MSA. a-synuclein -positive glial cytoplasmic inclusions (GCIs) are the major hallmark of MSA pathology and show wide-spread distribution in the CNS, which correlates with the degree of neurodegeneration in the striatonigral and olivopontocerebellar systems. The origin of a-synuclein in MSA oligodendroglia is still unclear, but the pathogenic role of GCIs is unequivocal. To this end extensive experimental stud-ies confirm that oligodendroglial a-synuclein opathy may trigger progressive neuronal loss, reactive gliosis, and myelin degeneration. Transgenic mouse models with overexpression of a-synuclein in oligodendrocytes, using selective oligodendroglial promotors have been a major tool to evidence the role of oligodendroglial a-synuclein opathy.

Oligodendroglia Nadia Stefanova Associate Professor Department of Neurology Medical University of InnsbruckAustria


Abstracts

Targeting AS Levels through Lysosomal Enzymes (CTSD,GBA1)

Michael G. Schlossmacher, M.D.Bhargava Research Chair in NeurodegenerationProgram in Neuroscience, Ottawa Hospital Re-search InstituteDivision of Neurology, The Ottawa HospitalUniversity of OttawaCanada

In the presentation “Targeting alpha-synuclein levels”, I shall focus on recent work conducted in our laboratory as well as by other investigators to elucidate lysosomal enzymes that may play a role in the normal breakdown of alpha-synuclein, which has become a logical target for cause di-rected therapy. Such enzymes, once validated, could be further exploited as platforms to reduce either the total concentration of alpha-synuclein, or a subset of its total pool, in an effort to modify neurodegenerative diseases that are associated with the misprocessing and accumulation of alpha-synuclein in the brain. Specifically, I will review both recently published and still unpublished results from investigations into the in vivo effects of two lysosomal enzymes, cathepsin D and acid beta-glucosecerebrosidase (GBA1).

Multiple system atrophy (MSA) is hallmarked by the development of alpha-synuclein (AS) fibril rich glial cytoplasmic inclusions in oligodendrocytes along with a strong neurodegeneration of select neuronal populations. Oligodendrocytes does not normally express AS. The presentation will dem-onstrate stages of oligodendroglial cytopathology before and after AS accumulation and aggrega-tion and relate these findings to models studies that tend to focus. Recent findings on disease as-sociated gene expression and cytokine signaling will be discussed.

Subsequent Steps to AS Aggregation in MSA

Poul Henning Jensen Professor Biomedicine Aarhus UniversityDenmark


Abstracts

The misfolding and aggregation of a-synuclein (αSyn) is linked to the pathology of Parkinson’s dis-ease,. Therapeutic targeting of αSyn by small molecules has been a major challenge because of its heterogeneous conformational states. Our studies for the first time show evidence that drug-like small molecules can bind to the monomeric solution state of αSyn and thereby can affect aggrega-tion propensity of the protein. We applied a biophysics based high throughput binding screen using chemical microarray surface plasmon resonance (SPR) (Neumann, T. et al. Let. Drug Des. & Discov. 2005, 2, 563) to identify small molecules that interact with monomeric αSyn. Our screen identified multiple binders of αSyn comprising diverse scaffolds with drug-like properties.. Next, these αSyn binding compounds were tested for their ability to inhibit αSyn aggregation in vitro and for impact on synuclein mediated disruption of cellular vesicular dynamics. A few of the compounds inhibit aggregation of αSyn robustly and a non-overlapping set restored normal vesicular function in cells overexpressing a-synuclein .. These results suggest that targeting monomeric αSyn by small mol-ecules represents a potentially fruitful approach for the development of small molecule therapeutics for Parkinson’s disease and related conditions.

A pathological hallmark of Parkinson disease is the presence of proteinaceous inclusions, called Lewy bodies that are enriched with a-synuclein . Molecular chaperones, such as heat shock protein 70 (Hsp70), are also found in Lewy bodies. Hsp70 expression enhances degradation of misfolded a-synuclein , reduces oligomer formation, and thereby ameliorates toxicity in models of a-synuclein overexpression. Furthermore, direct pharmacological upregulation of Hsp70 with the Hsp90 inhibi-tor, geldanamycin, results in decreased cytotoxicity due to a-synuclein . Although geldanamycin and its derivatives have potent effects, they are limited due to toxicity, brain permeability, and scaffold-ing. We recently described the effects of a novel class of potent, small molecule Hsp90 inhibitors on a-synuclein degradation, oligomer formation, and toxicity in a cellular model of synuclein over-expression. Screening yielded several candidate compounds that significantly reduced a-synuclein oligomer formation and cytotoxicity associated with Hsp70 induction.

One of these compounds, SNX-0723, showed favorable pharmacokinetics, brain permeability, and induction of Hsp70. These findings prompted the studies herein to determine whether chronic treat-ment with Hsp90 inhibitors can protect against a-synuclein dependent toxicity in the rat nigrostriatal system. Rat substantia nigra was injected unilaterally with AAV8 expressing human a-synuclein . Post injection rats were treated for 6 or 8 weeks by oral gavage with novel Hsp90 inhibitors, and then assessed for nigral dopamine cell loss, striatal tyrosine hydroxylase expression, and dopamine

Targeting Native AS using Pharmacological Chaperones and Aggregation Inhibitors

Targeting HSPs to Modulate AS Toxicity

Lisa McConlogue Distinguished Research Fellow Exploratory Research Elan PharmaceuticalsUSA

Pamela McLeanAssociate Professor Dept of Neuroscience Mayo Clinic FloridaUSA


Very encouraging proof of principle studies have been published pointing towards the potential use of alpha-synuclein antibodies in the treatment of Parkinson’s Disease and Dementia with Lewy bod-ies (Masliah E. et al., PLoS ONE, 2011; Bae E-J et al., J. Neurosci., 2012).

In theory alpha-synuclein antibodies do have the potential to counteract many aspects of alpha-synuclein toxicity, ranging from prevention of the prion like spread and seeding of disease pathology, decreasing inflammation and/or increasing clearance of intracellular pathological alpha-synuclein. In practice not enough data is available in order to select the profile of the alpha-synuclein antibody with the highest likelihood of success in a clinical trial.

Different approaches towards obtaining this understanding will be discussed. Both fundamental characteristics as the epitope of alpha-synuclein recognized by the antibody, the affinity of the an-tibody and specificity towards monomeric versus oligomeric/fibrillar forms of alpha-synuclein are important, but also the model systems selected for comparative studies of several different alpha-synuclein antibodies are of key importance

content. The first compound, SNX-0723, was well tolerated at 3 mg/kg, but did not reduce dopa-minergic toxicity in the substantia nigra compared to vehicle. Higher dose SNX-0723 (6-10 mg/kg) showed no rescue and resulted in systemic toxicity, weight loss, and early death. A second, more potent compound, SNX-9114, was better tolerated, but did not significantly reduce a-synuclein de-pendent nigrostriatal toxicity. Interestingly, analysis of striatal dopamine content indicated a rescue in alpha-synuclein induced dopamine depletion by novel the Hsp90 inhibitors suggesting a possible positive effect on neurochemical plasticity in striatal terminals. Although the compounds still appear limited by potential toxicity, our findings demonstrate efficacy of oral treatment and possible ben-eficial effects of these novel Hsp90 inhibitors in a vertebrate model of Parkinsonism that warrant further investigation.

Using Immunization to Counteract AS Toxicity Karina Fog Head of Department Neurodegeneration 1 H. Lundbeck A/SDenmark

Abstracts


Poster Presentations

Purpose: Understanding how genetic risk variants influence gene expression in different brain re-gions has become of key importance. One of the present examples is to have a better understand-ing of the PD mechanism and LRRK2 . In addition, there are significant PD risk loci have been identi-fied and replicated in GWAS studies such as MAPT locus. In this project investigate the correlation between genetic SNPs and gene expression and splicing regulation in control post-mortem human brain tissues from 10 different regions, which support different functional roles. The regions present-ed here are frontal cortex, temporal cortex, occipital cortex, white matter, hippocampus, thalamus, putamen, substantia nigra, medulla and cerebellum.

Material and Methods: 1231 RNA samples from 134 control human post-mortem brains were ex-tracted. The QC assessed RNA samples were run on Affymetrix GeneChipÂ® human Exon 1.0 ST Arrays. QC assessed arrays were analysed using Partek Genomic suite software. In parallel, DNAs from brains were run and analysed using the Illumina Omni 1M Beadchips [5]. A regression corre-lation analysis was performed using Matrix eQTL to identify gene expression and alternative exon splicing expression in different brain regions. The results have been validated using Quantigene as a novel non-PCR based technique.

Results: Our results showed some QTLs have stronger effect on specific group of regions together than others such as cortical regions. In addition, detailed investigation of the role of LRRK2 muta-tions in modulating gene expression or/and splicing in controls in different brain regions is applied. Significant regional differences for LRRK2 expression at mRNA and protein levels were shown. Im-munohistochemistry showed specific localization of LRRK2 protein expression in astrocytes as well as neurons. Furthermore, we have an exon QTLs correlate with the expression of specific exons located in functional protein domains of LRRK2.

Furthermore, our results for MAPT showed an exon QTL associated with an increase of exon 3 expression level on the minor haplotype of MAPT (H2) in all grey matter brain regions (P < 4.7 x10-6). This is not the case in white matter. This data suggest that the inclusion of exon 3 is protective against Parkinsons disease. However, the differential effect on MAPT transcripts do not allow us to determine whether this differential effect relates to different protein isoforms or to different cellular addressing of mRNA transcripts.

Conclusions: In addition to the novel regional specific QTLs, this study yields insights into how dif-ferent brain

Daniah Trabzuni1, 2, Mina Ryten1, Robert Walker3, Colin Smith3, Adaikalavan Ramasamy 4, Michael Weale4, John Hardy11 Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK.2 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia3 MRC Sudden Death Brain Bank Project, University of Edinburgh, Edinburgh, EH8 9AG, Scotland, UK.4 King’s College London, Guy’s Hospital, London SE1 9RT, UK.

The role of genetic variations on gene expression and splicing in multiple regions in control human post-mortem brain tissue: LRRK2 and MAPT in relation to PD

Daniah Trabzuni Genetic researcherInstitute of Neurology, UCLUnited Kingdom



Abstract: Î±-Synuclein (Î±SYN) is genetically and neuropathologically linked to a spectrum of neurode-generative diseases including Parkinsons disease, dementia with Lewy bodies, and related disorders. Cognitive impairment is recapitulated in several Î±SYN transgenic mouse lines. However, the mechanisms of dysfunction in affected neurons are largely unknown.

Purpose and Methods: Here we measured neuronal activity induced gene products in the limbic system of Î±SYN transgenic mice upon fear conditioning.

Results: Induction of the synaptic plasticity marker c-Fos was significantly reduced in the amygdala and hippocampus of (Thy1)-h[A30P]Î±SYN transgenic mice in an age-dependent manner. Similarly, the neuronal activity inducible polo-like kinase 2 (Plk2) that can phosphorylate Î±SYN at the pathological site serine-129 was up-regulated in both brain regions upon fear conditioning. Plk2 inductions in the amygdala after FC were paralleled by a small but significant increase in the number of neuronal cell bodies immu-nopositive for serine-129 phosphorylated Î±SYN in young but not aged (Thy1)-h[A30P]Î±SYN transgenic mice. In addition, we observed in the aged hippocampus a distinct type of apparently unmodified trans-genic Î±SYN profiles resembling synaptic accumulations of Î±SYN.

Conclusion: The cognitive decline observed in aged Î±SYN transgenic mice might be due to impairment of neurotransmission and synaptic plasticity in the limbic system by distinct Î±SYN species.

Ethics Agreement: The behavioral tests and brain dissections were in compliance with the authorization N10/08 licensed by the regional board (RegierungsprÃ¤sidium) TÃ¼bingen and were performed accord-ing to the German law, Guide for the Care and Use of Laboratory Animals.

This work was supported by the Helmholtz Alliance â€œAging Brainâ€�, the German Center for Neurode-generative Diseases and the Hertie Foundation.

Heinrich Schell1,2, Cindy Boden2, AndrÃ© Maia Chagas3, Philipp J. Kahle1,2,3*(Laboratory of Functional Neurogenetics, Department of Neurodegeneration, 1Hertie Institute for Clinical Brain Research and 2German Center for Neurodegenerative Diseases, and 3Graduate School of Cellular and Molecular Neuroscience, University of TÃ¼bingen, Germany)

Impaired c-Fos and Polo-like Kinase 2 Induction in the Limbic System of Fear-conditioned Î±-Synuclein Transgenic Mice

Heinrich SchellScientific AssistantDZNE Tuebingen Germany



Objective: It is becoming evident that the peripheral immune system takes an active role in Parkinson’s Disease (PD) progression, as supported/suggested by the induction of the antigen presenting protein HLA-DR (human homolog to MHC II) in diseased brain and the infiltration of lymphocytes; as well as the presence in serum of alpha-synuclein specific antibodies. We designed a vaccination strategy to attempt to harness these processes and mediate protection against disease progression in a rat model of PD.

Methods: Using recombinant adeno-associated viral vector (rAAV) we unilaterally over-expressed human alpha-synuclein in the rat substantia nigra (SN) to induce progressive neuropathology. Prior to stereotacti-cal delivery of rAAV-alpha-synuclein, animals were vaccinated in order to induce a memory T cell popula-tion against the protein.

Results: This therapeutic approach resulted in the accumulation of CD4+ MHC II+ ramified microglia in the SN, long lasting infiltration of CD4+Foxp3+ cells throughout the nigrostratial system, and 66% fewer pathological aggregates in the striatum compared to control animals that received a mock vaccine. These events were correlated with the long-term increase in GDNF levels in the striatum (8 weeks post-virus injection).

Conclusions: Together, these results show that a protective vaccination strategy requires the induction of regulatory T cells and distinctly activated microglia (CD4+ MHC II+) that induce immune tolerance against alpha-synuclein.

A. Annibali: Master Student in the area of neuroscience.M.Romero-Ramos: an established neuroscientist and pioneer of the AAV-a-syn PD model, she has characterised the model across species. She is a specialist in neuroinflammation and a-syn post-translational modifications in PD and how they affect PD pathology progression.

Objective: To investigate whether selective serotonin reuptake inhibitor (SSRI) has therapeutic value in glottic stenosis of patients with synucleinopathy, multiple system atrophy (MSA).

Background: Few therapeutic options are currently available for glottic stenosis in patients with MSA. Ex-perimental data have shown that medullary serotonergic neurons have been reported to exert tonic drive to provide spontaneous activity in the dilator muscles of the glottis, which maintain glottic opening during

Î±-Synuclein vaccination prevents the accumulation of PD-like pathological inclusions in striatum via Treg recruitment.

Selective serotonin reuptake inhibitor emerges as the therapeutic agent in the manage-ment of glottis stenosis in synucleinopathy

Vanesa Sanchez-GuajardoAarhus UniversityDenmark

Tetsutaro OzawaDepartment of Neurology, Brain Research Institute, Niigata UniversityJapan


respiration. Of note, depletion of medullary serotonergic neurons has recently been identified in the brains of patients with MSA. These findings suggest that serotonergic neurotransmission functionally related to glottic opening is compromised in patients with MSA. Therefore, pharmacological interventions that have therapeutic value in relation to augmenting serotonergic neurotransmission should be considered in MSA patients. Methods: Fiberoptic laryngoscopy was performed under sedation in 3 patients with MSA before and after initiation of SSRI therapy. The therapy was performed using paroxetine taken orally according to the protocol, as follows: 10 mg/day for the first week; 20 mg/day for the second week; and 30 mg/day as the maintenance dose. The degree of glottic stenosis was assigned as follows: absent, 0; mild, 1+; moderate, 2+; and severe, 3+. Results: Case 1 showed glottic stenosis under sedation rated as 3+, reduced to 1+ after 58 weeks of therapy. Case 2 showed stenosis rated as 2+, reduced to 1+ after 25 weeks of therapy. In Case 3, stenosis was 2+ before and after treatment, but response of glottic opening to continuous positive airway pressure was improved after 23 weeks of therapy. Conclusions: The results of the present study raise the possibility that SSRI therapy can ameliorate glottic stenosis in patients with MSA for certain periods of time. Because SSRI has been reported to inhibit cell-to-cell propagation of alpha-synuclein pathology, our observation points to the need for further investigation to elucidate the mechanism of the SSRIâ€™s effect on glottis stenosis in MSA patients. (This study was presented in the 16th International Congress of Parkinson’s Disease and Movement Disorders, and was published in Move-ment Disorders 2012;27(7):919-21.)

Evidence of Ethical Approval: Informed consent was obtained from all participants. The protocol of this study was approved by the Ethics Committee at Niigata University School of Medicine.

Tetsutaro Ozawa (1), Kanako Sekiya (1), Yumi Sekine (1), Takayoshi Shimohata (1), Masahiko Tomita (2), Hideaki Nakayama (3), Naotaka Aizawa (2), Ryoko Takeuchi (1), Takayoshi Tokutake (1), Shinichi Katada (1), and Masatoyo Nishizawa (1)

(1) Department of Neurology, Niigata University Brain Research Institute, Niigata, Japan(2) Department of Otolaryngology and (3) Division of Respiratory Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.


Abstract Background: Intraneuronal inclusion composed of aggregated alpha-synuclein (aS), called Lewy body (LB), is known as the pathological hallmark of Parkinsons disease (PD). Recent studies have shown that the transcellular spreading of fibrillar aS occurrs both in vitro and in vivo; however, the precise molecular mechanisms underlie the internalization of extracellular aS still remain unknown. Meanwhile, Nedd4 (neural precursor cell expressed developmentally down-regulated protein 4), an E3 ubiquitin ligase, had been shown to catalyze the K63-linked ubiquitination of aS. Since numerous cell-surface receptors require the modification of K63-linked ubiquitination for the proper targeting to endosome, we explored the possible role of Nedd4 in the internalization step of aS using cultured cells.

Methods: Wild type or active site dead mutant human Nedd4 was overexpressed in HEK293T cells us-ing FuGENE HD (Roche). Because PS motif, which was recognized by Nedd4, is located in the carboxyl terminus of aS (residues 120â€“133), we generated deletion mutants including delta-PS1 (1-119, 129-

Nedd4 E3 ubiquitin ligase facilitates the endosomal targeting of alpha-synuclein

Naoto SugenoDepartment of Neurology, Tohoku University School of MedicineJapan



Abstract Background: The main pathologies of Parkinson’s disease (PD) are a restricted loss of the nigrostiatal system and the increasing deposition of S129 phosphorylated alpha-synuclein (phospho-syn).

Purpose:To determine if the levels of PD-associated kinases change in association with increasing phos-pho-syn in PD.

Methods: Brain tissue from 24 PD cases at different disease stages (early stage n=8, mid-stage n=9, late stage n=7) and 7 controls was obtained from the Australian Network of Brain Banks following insti-tutional approvals. 500mg of frozen putamen (severely affected) and frontal cortex (affected late) was homogenized and fractionated (TBS-soluble, SDS-soluble). The levels of phospho-syn and five associated kinases (PLK-1, PLK-2, CK-II, S935P-LRRK2/total-LRRK2 and GAK) were evaluated by semi-quantitative western blotting using specific antibodies. Multivariate analyses (P

Results: 1) In the PD putamen, increasing phospho-syn correlated with SDS-soluble PLK-2, with both in-creasing with increasing disease stage, 2) in the PD cortex, there were no associations between phospho-syn and kinase levels, although there was a significant increase of TBS-soluble PLK-2, with decreasing levels as the disease progresses, and 3) LRRK2 was decreased in PD putamen and frontal cortex, with increasing frontal LRRK2 as the disease progresses,.

Changes in Parkinson’s disease-associated kinases levels associate with increasing S129 phosphorylated alpha-synuclein in Parkinson’s disease

Jinxia ZhouAlpha-synuclein phosphorylation and kinasesNeuroscience Research Australia and University of New South WalesAustralia

140), delta-C (1-119), and delta-PS2 (1-119, 134-140). All recombinants were expressed in BL21 E. coli. and further purified by the bulk GST purification module (GE Healthcare). In vitro ubiquitinylation assay for recombinant aS was performed using immunoprecipitated Nedd4 as E3 ligase. UbcH5b, strongly associ-ated with Nedd4 ubiquitinylation was used as E2 conjugating enzyme. To observe the internalization of extracellular aS, cells treated with different aS recombinants were fractionated and subjected to Western blot analysis.

Results: Wild type (wt) but not delta-PS1, delta-PS2, nor delta-C were K63-linked ubiquitinated by Nedd4 in vitro. wt-aS was more efficiently internalized and localized in endosomal compartment compared to the deletion mutants both in HEK293T and SH-SY5Y cells. The exogenous expression of Nedd4 led to the SDS-resistant aS oligomers in the endosomal fraction. Likewise, the co-localization of aS-positive aggre-gates and endosomal resident proteins was observed by immunostaining. Co-IP experiment showed that PS motif of aS is indispensable for the physiological interaction between Nedd4 and aS.

Conclusions: Nedd4-linked K63 ubiquitinylation may be coupled with the internalization step of aS as well as its targeting to endosome. The 120-128 amino acid residue at the C-terminus of aS is required to the Nedd4-mediated ubiquitin modification.


Conclusions: The data show significant changes in the levels of different kinases in PD brain and show that the PLK-2 is the only kinase that increases with increasing phospho-syn. The unexpected decrease in LRRK2 may relate to early synaptic toxicity, although recent studies have shown reduced mRNA in PD.

Abstract Purpose: Multiple system atrophy (MSA) is a sporadic and rapidly progressive neurodegenera-tive disorder that presents clinically with autonomic failure in combination with parkinsonism or cerebellar ataxia. The pathological hallmark of MSA is the aggregation of misfolded Î±-synuclein in oligodendrocytes and subsequent disintegration of myelin, which is composed of 78% lipid. How oligodendrocytes regulate lipid production and maintain myelin is unknown. We have evidence that the lipid transporter ABCA8 regu-lates lipid production in oligodendrocytes and is associated with brain myelination. We hypothesise that the function of ABCA8 is dysregulated in MSA brain.

Method: Frozen brain tissue from 8 MSA and 10 age- and gender-matched control cases was supplied from the New South Wales Brain Banks following institutional approvals (see Acknowledgements). RNA was isolated from approximately 50 mg of brain tissue from disease-affected (putamen and white mat-ter of the pons and motor cortex) and unaffected (anterior cingulate and visual cortices) regions and converted into cDNA. Quantitative PCR (qPCR) assay was carried out using a Mastercycler ep realplex S (Eppendorf) and the fluorescent dye SYBR Green. ABCA8 gene expression was normalized to the house-keeper gene beta-actin and calculated using the comparative threshold cycle value method. Following the assessment of ABCA8 expression, we then tested the impact of ABCA8 on Î±-synuclein expression in oligodendrocytes. We transfected human MO3.13 oligodendrocytes, cultured in 12-well tissue culture plates, with human ABCA8 cDNA and measured the expression of Î±-synuclein by qPCR (n=6).

Results: ABCA8 expression was significantly elevated (2.9â€“5.2 fold; p

Conclusion: These results show elevated ABCA8 in MSA brains in regions with Î±-synuclein-positive oligodendroglia, and that increased ABCA8 expression upregulates oligodendroglial expression of Î±-synuclein. Overall this data implicates increased ABCA8 expression in the generation of MSA pathology.

Acknowledgements: This research was supported by the National Health and Medical Research Council of Australia (NHMRC). Brain tissue was received from the Sydney Brain Bank at Neuroscience Research Australia and from the New South Wales Tissue Resource Centre at the University of Sydney, which are supported by the NHMRC, the University of New South Wales, Neuroscience Research Australia, Schizophrenia Research Institute and the National Institute of Alcohol Abuse and Alcoholism (NIH (NIAAA) R24AA012725). Ethics approval was from the University of New South Wales Human Research Ethics Committee.

Altered Expression of ABCA8 in Multiple System Atrophy Brain

Woojin S. KimNeuroscience Research AustraliaAustralia



Abstract Purpose: The aim of this study was to investigate a family with autosomal dominantly inherited young onset PD using genetic and neuropathological methods and to document the clinical features in the affected family members.

Method: Brain donation by the proband enabled a detailed post-mortem neuropathological examina-tion including immunohistochemical and double immunofluorescence microscopy of paraffin embedded brain tissue. The regional and cellular distribution of pathological features was analysed. Whole exome sequencing was performed to investigate the underlying genetic cause of the disease. Medical records review provided details of the disease course in family members

Results: Whole exome sequencing of available DNA from the proband revealed a G51D mutation in the alpha-synuclein gene SNCA and this was confirmed in his affected sister to segregate with disease. The mutation did not occur in control cases. Post-mortem brain examination of the proband revealed moder-ate frontal and severe anterior temporal lobe atrophy. Semi-quantitative assessment of histological chang-es identified the greatest severity of neuronal loss in the temporal and insular cortices, the amygdala, the CA2-3 of the hippocampus, substantia nigra, locus coeruleus and the dorsal motor nucleus of the vagus. Neuronal cytoplasmic alpha-synuclein inclusions were widespread and were detected along with thread-like structures. Oligodendroglial inclusions similar to those observed in MSA were also a feature. All inclusion types were ubiquitin and p62-positive and were labelled with an antibody which specifically recognised alpha-synuclein phosphorylated at the Y125 epitope. In addition, TDP-43 immunoreactive in-clusions were observed in limbic regions and in the striatum.

The proband had an age at disease onset of 19 years, with juvenile parkinsonism initially presenting with tremor in the left arm, then right arm followed by progressive akinesia and rigidity, later developing cog-nitive impairment and bulbar dysfunction with dysarthria and dysphagia. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive young-onset Parkinson’s disease with onset in their late thirties. These clinical features also show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation.

Conclusion:In conclusion we describe a familial alpha-synucleinopathy with neuropathological features characteristic of both Parkinson’s disease and multiple system atrophy. Investigation of the disease mech-anism underlying the G51D SNCA mutation could aid in understanding of alpha-synuclein biology and its impact on disease phenotype.

Synucleinopathy with a G51D alpha-synuclein mutation: A neuropathological and genetic study Aoife Kiely

Genetics of Synucleinopathies/ Neuronal alpha-synu-clein pathology/ Non-neuronal alpha-synuclein pathology, UCL institute of Neurology, LondonUnited Kingdom



Purpose: Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic dysfunction. The pathological hallmark of MSA is the glial cytoplasmic inclusions (GCI) in oligodendrocytes, the main constituent of which is alpha-synuclein (aSyn), implying that this protein plays an important role in the pathogenesis of the disease. Alterations in SNCA gene expression may be one of the relevant disease mechanisms in MSA, although previous studies exploring expression levels of aSyn mRNA in MSA are limited in number, sample size and brain regions explored. The purpose of this study is to examine aSyn mRNA levels in MSA, Parkinsons disease (PD) and controls in brain regions known to have variable susceptibility to aSyn pathology in MSA.

Method: Frozen tissue from 5 MSA-Mixed, 5 MSA-SND, 5 MSA-OPCA subtypes, 5 PD and 4 normal con-trol cases were selected from the archives of the Queen Square Brain Bank (QSBB) for Neurological Dis-orders. Brain regions studied include the posterior frontal and occipital cortices, dorsal putamen, pontine base, and cerebellum. RNA was extracted using the Qiagen miRNeasy kit then reverse transcribed with SuperScriptÂ® VILOâ„¢ cDNA Synthesis Kit (Invitrogen, UK) according to manufaurerâ€™s instructions. qPCR was performed on Stratagene MX3000p (Agilent technologies, CA) using Power SYBR Green Mas-ter Mix (Applied Biosystems) as the detection method.

Results: Alpha-synuclein mRNA expression levels were evaluated in the posterior frontal and occipital cortices, dorsal putamen, pontine base, and cerebellum of MSA, IPD and control cases. The MSA group had the lowest level of expression and the IPD group the highest, however this did not reach statistical significance (p=0.14). When regional expression was analysed, a statistically significant difference was found (p

Conclusion: Alpha-synuclein mRNA expression is not significantly different between the MSA subgroups, IPD and control cases in all regions investigated. This indicates that control of aSyn transcription may not have a key role in the pathogenesis of MSA.

Yasmine Asi1, Henry Houlden2, 3, Andrew J. Lees1, 3, Tamas Revesz1 and Janice L. Holton11Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, UK. 2Department of Molecular Neu-roscience, UCL Institute of Neurology, UK.3Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK. Correspondence to: Dr Janice Holton MBChB, PhD, FRCPath, Department of Molecular Neuroscience, UCL institute of Neurology, Queen Square, London WC1N 3BG. Email: [email protected]

Alpha-synuclein expression in multiple system atrophy

Yasmine AsiPhD studentUCL institute of NeurologyUnited Kingdom



Purpose: Increased levels and aggregation of Î±-synuclein characterise Parkinson’s disease (PD). Î±-Synuclein is degraded primarily by chaperone-mediated autophagy (CMA) in lysosomes, a process thought to be dysfunctional in PD. More recent reports suggest a more global loss of lysosomes. To determine the effect of PD on lysosomes, we assessed the levels of CMA-specific, membrane and luminal lysosomal proteins in cortical regions without major neuron loss but with and without PD-specific Î±-synuclein deposi-tion.

Methods: Following study approvals, brain tissue from PD patients (N=9) and age-matched controls (N=10) was obtained from the NSW Brain Banks. Soluble and membrane-bound proteins were extracted from anterior cingulate (contains Î±-synuclein aggregates) and occipital (no aggregates) cortices and the relative protein levels quantified in Western blots using specific antibodies and computer-based software. Multivariate analyses were used to determine changes related to Î±-synuclein aggregation.

Results: Regions with PD aggregates showed increased membrane-associated Î±-synuclein (264% over controls, p=0.001), as expected, which was associated with reduced LAMP2a (CMA receptor, 76%, p=0.004), reduced Hsc70 (Î±-synuclein-specific CMA chaperone, 22%, p=0.003) and increased cath-epsins (A, B and D, 154-624%, pâ‰¤0.036). The cytosolic CMA substrates MEF2D and IÎºBÎ± were also increased in regions with PD aggregates (5-10 fold, pâ‰¤0.055), while LAMP1, LAMP3 and cathepsin K remained unchanged.

Conclusion: As some lysosomal proteins were not reduced in PD, specific degeneration of this cel-lular organelle as underlying or contributing to the pathology of PD is highly unlikely. Rather, our data show that in regions abnormally accumulating Î±-synuclein but without substantial cell loss, lysosomes are dysfunctional, as there is a selective reduction in the CMA membrane receptor and chaperone. The burden of increased Î±-synuclein on CMA machinery appears to impair the degradation of other known CMA substrates. There are also related alterations in lysosomal proteases that are likely to increase other lysosomal degradation pathways.

Ethical Approval and Funding Acknowledgements: Brain tissue was received from the Sydney Brain Bank at Neuroscience Research Australia and from the New South Wales Tissue Resource Centre at the University of Sydney, which are supported by the National Health and Medical Research Council of Aus-tralia (NHMRC), the University of New South Wales, Neuroscience Research Australia, Schizophrenia Re-search Institute and the National Institute of Alcohol Abuse and Alcoholism (NIH (NIAAA) R24AA012725). This study was approved by the Human Research Ethics Committee of the University of New South Wales and the Scientific Review Committee of the New South Wales Brain Banks. Funding was received from the NHMRC (grants 1008307 and 630752) and Neuroscience Research Australia.

Karen E. Murphy1, Antony A. Cooper2, Ellen Sidransky3, Glenda M. Halliday11Neuroscience Research Australia and School of Medical Sciences, University of New South Wales, Sydney, Australia; 2The Garvan Institute of Medical Research, Sydney, Australia; and 3National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

Decreased lysosomal autophagy rather than lysosomal degeneration associates with Î±-synuclein pathology in Parkinson’s disease Karen Murphy

MS, Neuroscience Research AustraliaAustralia



Abstract Purpose: Î±-synuclein is thought to play a crucial role in the pathogenesis of Parkinson disease (PD), as evidenced by clinical and laboratory findings. Although known as neuronal protein and found predominantly in presynaptic terminals, Î±-synuclein is also present in extracellular fluids, especially in cerebrospinal fluid at very low concentration. However, the role of extracellular Î±-synuclein is not well un-derstood. In this study, we examined the effect of nanomolar concentrations of extracellular Î±-synuclein on neuronal and microglial cells.

Methods: Human neuroblastoma SHSY-5Y cells and murine microglial BV-2 cells were used. Cells were treated with nanomolar concentrations of recombinant human Î±-synuclein, which was added to the me-dium, and cell viability was determined using MTT assay. To examine whether the change in the viability of SHSY-5Y was through increased proliferation or increased survival, BrdU immunocytochemistry was performed. The change in the release of inflammatory cytokine by BV-2 was evaluated using multiplex bead assay. Reactive oxygen species (ROS) production and nitric oxide (NO) production by BV-2 was also examined.

Results: In neurally differentiated SHSY-5Y cells, treatment with 50nM, 100nM, and 1Î¼M of Î±-synuclein increased cell viability. This increase in cell viability was not accompanied by increase in BrdU binding, sug-gesting increased neuronal survival rather than increased neuronal proliferation. In addition, pretreatment with 50nM and 100nM Î±-synuclein tended to protect SHSY-5Y cells against rotenone-induced neuronal death. In BV-2 cells, treatment with 10nM, 50nM, 100nM, and 1Î¼M of Î±-synuclein increased cell viability. However, the level of NO and ROS production and interleukin-6 secretion were not changed by treatment with 10nM, 50nM, and 100nM of Î±-synuclein. Tumor necrosis factor-Î± secretion was decreased by treat-ment with 50nM Î±-synuclein.

Conclusion: This study shows that extracellular Î±-synuclein at nanomolar concentrations increases neuronal cell survival, which may have implications for the pathogenesis and therapy for PD. Nanomolar extracellular Î±-synuclein also increases cell viability of microglial cells, but its significance is not clear. Interestingly, the production of inflammatory mediators was not increased or even decreased with na-nomolar concentrations of Î±-synuclein. Further studies are needed for the elucidation of the molecular mechanism involved.

Effect of nanomolar concentrations of extracelluar alpha-synuclein on neuronal and microglial cells

Han-Joon KimSeoul National University HospitalKorea, (South Korea)



Parkinson’s Disease (PD) is a complex, progressive neurodegenerative disorder for which neither a cure nor effective long-term therapy exists while the lack of knowledge of the molecular mechanisms responsi-ble for PD development is a major impediment to therapeutic advances. The protein Î±Synuclein is a cen-tral component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and our research has discovered that Î±Synuclein and mitochondrial dysfunction have a negative synergistic inter-relationship. Using both yeast and mammalian Î±Synuclein cell models of PD we have found that impairment of different complexes of mitochondrial oxidative phosphorylation (OXPHOS) renders cells very sensitive to Î±Synuclein expression levels while elevated levels of Î±Synuclein can result in mitochondrial dysfunction. This negative relation-ship results in the synergistic production of reactive oxygen species (ROS)/oxidative stress, as well as the initiation of an endoplasmic reticulum (ER) stress response. Investigations are ongoing into what role, if any, that autophagy (including macroautophagy and mitophagy), ER-Golgi trafficking and calcium homeo-stasis may have in the cellular stress and death cascade, resulting from this synergistic interrelationship and how these relate to PD.

Mitochondrial dysfunction and Î±Synuclein toxicity may exacerbate each other in a self-amplifying cycle that, over prolonged periods of time, could finally attain a level of damage that contributes to the ob-served pathology and account for the late onset nature of the disease.

Charmaine Lang (1), Stephanie Kong (1), Kathryn Hill (1) & Antony Cooper (1,2)Affiliation: 1= Garvan Institute of Medical Research; 2= School of Biotechnology and Biomolecular Science, University of New South Wales.

Aim: To investigate the molecular basis for Î±-Synuclein (Î±SN) oligomers effect on cellular calcium ho-meostasis and how the endoplasmic reticulum calcium ATPâ€™ase dysfunction is involved.

Methods: We conducted a proteomic screen for oligomer specific ligands in porcine brain extracts by supplementing the extracts with oligomeric Î±SN and as negative controls monomeric Î±SN or buffer, fol-lowed by co-immunoprecipitation of the Î±SN with associated ligands. Immunoprecipitates were resolved by SDS-PAGE followed by liquid chromatography tandem mass spectrophotometry of tryptic peptides.

Results: One of the found targets was the sarcoplasmic/endoplasmic calcium ATPase 2 (SERCA; gi|47523128). The Î±SN oligomer selective binding was validated by western blotting. Immunohistochem-ical analysis demonstrated the presence of SERCA in the core of purified human Lewy bodies. SERCA is

Mitochondrial OXPHOS dysfunction and alpha synuclein: a pathogenic partnership in Parkinson’s Disease

Soluble aggregates of alpha-Synuclein stimulates the endoplasmic reticulum Ca(2+) ATPase and induce toxic cellular calcium disturbances

Antony CooperAssoc ProfessorGarvan Institute of Medical Reseach Australia

Cristine BetzerMSc, Aarhus UniversityDenmark



an ATP-consuming calcium ion pump residing in the endoplasmic reticulum (ER) pumping Ca2+ into the ER lumen and thus maintaining low cytolic Ca2+ levels. In vitro investigations using microsomal SERCA1A purified from rabbit muscle and ER purified from COS cells demonstrate oligomeric AS increases ATP hydrolysis compared to monomer AS and buffer controls. This increase was blocked by AS specific anti-bodies. The oligomer did not induce apparent pore formation measured by the efflux of 45Ca from rabbit muscle microsomes compared to monomer and buffer controls. The effect on cellular calcium homeosta-sis is currently being investigated and will be presented.

Conclusion and Perspective: Oligomerization of AS induce a gain of function causing a stimulation of SERCA activity, which influences the cytosolic calcium homeostasis and ATP hydrolysis. Few other pro-teins have been described to affect the activity of SERCA, but all of them reduce the ATPase activity. Cur-rent investigation focuses on the cytoprotective potential of modulating Ca2+ levels in our oligodendro-cyte cell model of Î±SN aggregate- and S129-phosphorylationdependent toxicity (OLN cells co-expressing Î±SN and p25) and in hippocampal neurons from Thy1-human AS expressing mice and AS knockout mice.

Funding: MJFF RRIA 2008, Aarhus University PhD grant, The Lundbeck Foundation

Betzer, C. Aarhus University, Dept. of Biomedicine, Aarhus, Zheng, J. Aarhus University, Dept. of Biomedicine, Aarhus, Andersen, J.P. Aarhus University, Dept. of Biomedicine, Aarhus, GAi, W.P. Flinders University, School of Medicine, Adelaide, Australia. Stensballe, A. Aalborg University, Department of Biotechnology, Chemistry and Environmental Engineering, Section of Biotechnology, Aalborg, Jensen, P.H. Aarhus University, Dept. of Biomedicine, Aarhus

Purpose: To develop and characterize monoclonal antibodies that specifically recognizes alpha-synuclein aggregates (oligomers or fibrils).

Methods: Balb/c female mice were immunized with alpha-synuclein, at 3 weeks interval. Splenocytes isolated from mice with high titers were fused with Sp2/O myeloma cells to generate hybridoma clones. Positive clones were identified by ELISA. Dot blot assay was carried out to select clones specific for alpha-synuclein aggregates. Monoclonal antibodies (mAbs) were purified from culture supernatants using protein-G affinity chromatography and characterized by inhibition ELISA, dot blot and immunohistochemi-cal analysis.

Results: Fusion carried out using splenocytes from mice immunized with alpha-synuclein resulted in around 1100 clones. We selected 6 mAbs namely Syn-F1, Syn-F2, Syn-O1, Syn-O2, Syn-O3 and Syn-O4. Using inhibition ELISA these mAbs showed high affinity to alpha-synuclein aggregates than the monomers. Their specificity towards alpha-synuclein was also confirmed by dot blot assay. Our mAbs reacted specifi-cally to alpha-synuclein fibrils and did not react to any other amyloid fibrils. Importantly our mAbs stained specifically Lewy bodies and Lewy neurites found in PD and DLB brain sections as performed by four independent research groups.

Development and Characterization of Specific Monoclonal Antibodies against Alpha-synuclein Aggregates

Nishant Narayanan VaikathResearch AssistantDepartment of Biochemistry, UAE UniverstiyUnited Arab Emirates



Multiple system atrophy is a parkinsonian neurodegenerative disorder. It is cytopathologically character-ized by accumulation of the protein p25Î± in the cell bodies of oligodendrocytes followed by accumulation of aggregated Î±-synuclein in so-called glial cytoplasmic inclusions. p25Î± is a stimulator of Î±-synuclein aggregation, and coexpression of Î±-synuclein and p25Î± in the oligodendroglial OLN-t40-AS cell line causes Î±-synuclein aggregate-dependent toxicity. In this study, we investigated whether the FAS system is involved in Î±-synuclein aggregate dependent degeneration in oligodendrocytes and may play a role in multiple system atrophy.

Using rat oligodendroglial OLN-t40-AS cells we demonstrate that the cytotoxicity caused by coexpressing Î±-synuclein and p25Î± relies on induction of the death domain receptor FAS and caspase-8 activation. Using primary oligodendrocytes derived from Î±-synuclein transgenic mice we demonstrate that they exist in a sensitized state expressing pro-apoptotic FAS receptor, which makes them sensitive to FAS ligand-mediated apoptosis. Immunohistochemical analysis demonstrated enhanced FAS expression in multiple system atrophy brains notably in oligodendrocytes harboring the first evidence of glial cytoplasmic inclu-sions. Immunoblot analysis show an increase in FAS in brain extracts from multiple system atrophy cases. Oligodendroglial expression of Î±-synuclein leads to oligodendrocyte dysfunction involving FAS induction and this may play a pathophysiological role in multiple system atrophy.

In MSA, oligodendroglial FAS expression is an early hallmark of oligodendroglial pathology in MSA that mechanistically may be coupled to Î±-synuclein expression.

Christine L. Kragh, GwenaÃ«lle Fillon, Amanda Gysbers, Hanne D. Hansen,Louise Berkhoudt Lassen, Manuela Neumann, Christi-ane Richter-Landsberg, Christian Haass, Bernard Zalc, Catherine Lubetzki, Wei-Ping Gai, Glenda M. Halliday, Philipp J. Kahle, Poul H. Jensen.

FAS-dependent cell death in Î±-synuclein transgenic oligodendrocyte models of multiple system atrophy

Louise Berkhoudt LassenAarhus UniversityDenmark

Poster PresentationsConclusions: We developed novel mAbs that are specific to alpha-synuclein aggregates, which can be extremely useful tools for research, biomarker development and diagnosis of Parkinson’s disease pathol-ogy.

N.N. Vaikath1, 2, N. Majbour1, M.T. Ardah1, S. Varghese1, G. Halliday3, W. Gai4, W. van de Berg5, L. Parkkinen6, M.E. Haque1, J.Y. Li2, O.M. El-Agnaf1


Abstract Purpose: Multiple System Atrophy (MSA) is a sporadic, adult-onset, neurodegenerative dis-ease of unknown etiology. Its clinically progressive course is characterized by a variable combination of parkinsonism, cerebellar ataxia and/or autonomic dysfunction. MSA is a member of a diverse group of neurodegenerative disorders termed Î±-synucleinopathies due to the presence of abnormal Î±-synuclein positive cytoplasmic inclusions in oligodendrocytes, glial cytoplasmic inclusions (GCI). Î± -synuclein is a protein that is encoded by the SNCA gene in humans. Alternative SNCA splicing gives rise to four isoforms (SNCA140, SNCA126, SNCA112, and SNCA98). Moreover, other proteins, parkin and synphilin-1 are also involved in the development of other synucleinopathies: Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It has been widely hypothesized that loss of parkin function alters the degradation of some unfolded proteins by proteasomes and induces the accumulation of their substrates which leads to the degeneration of dopaminergic neurons. Synphilin-1 interacts with Î±-synuclein and ubiquitination of synphilin-1 was shown to be mediated by parkin.

Because the Î± -synuclein, as well as parkin and synphilin isoforms show differential expression changes in PD and DLB, we studied the protein expression levels in selected areas of MSA brains (substantia nigra, putamen, cerebellum cortex, and nucleus dentatus).

Method: The differential expression of four Î±-syn (SNCA-140, SNCA-126, SNCA-112, SNCA-98), seven parkin-2 (TV1, TV2, TV3, TV6, TV7, TV11, and TV12), and four synphilin-1 (SNCAIP1, SNCAIP1A, SN-CAIP1B, SNCAIP1C) isoforms was ascertained by the use of isoform-specific primers and relative expres-sion analysis with SybrGreen and beta-actin competimer technology.

Results: SNCA- 140 and SNCA- 112 expression levels were significantly increased in MSA brains com-pared with controls, whereas expression levels of SNCA-126 were decreased in MSA vs. normal controls in all four brain areas. We did not observe changes in expression of SNCA-98 isoform. Moreover, MSA brains showed increased expression levels of parkin-2 TV12 isoform lacking N-terminal ubiquitin-like do-main and SNCAIP1A, an aggregation-prone isoform that causes neuronal toxicity.

Conclusion: Our findings may indicate that the shift in Î±-synuclein isoform ratios (decreased SNCA-126 in conjunction with increased SNCA-112 levels) could be instrumental in aggregation events. Î± -synuclein interaction with membranes is thought to be one of the steps preceding Î±-synuclein aggregation. SNCA-126 is characterized by the interruption of the domain responsible for proteinâ€“membrane interaction thus may be aggregation protective. SNCA-112 mainly constitutes five amphipathic helices which seem to make it to aggregate even more easily than SNCA-140. Moreover, alternatively spliced SNCA-112 activates complement, microglia, and astrocytes resulting in neuronal death in vitro suggesting that lo-cal inflammatory mechanisms could contribute to MSA pathogenesis. Furthermore, the increase levels of SNCA-126 in healthy control may point at SNCA-126 as an aggregation-preventing isoform in normal brains.

Expression of Alpha-Synuclein Splice Variants in Multiple System Atrophy Brains

Tomasz BrudekResearch Laboratory for Stereology and Neurosci-ence, Bispebjerg University Hospital Denmark



Small Compounds Extracted From Chinese Herbal Medicine Inhibit The Toxicity And The Formation of Early and Late Aggregates Of Î±-Synuclein

Mustafa Taleb Ardah PhD studentUnited Arab Emirates UniversityUnited Arab Emirates


In conclusion, distinctive isoform expression patterns of genes characterized previously in post-mortem samples of frontal cortex from DLB and PD brains appear also to play a role in MSA pathogenesis.

Purpose: The Chinese herbal medicines have been widely used for the treatment of symptoms relevant to Alzheimer disease (AD) and Parkinsons disease (PD) for centuries. In this study sixteen compounds ex-tracted from the Chinese herbal medicines (Chinese Medicinal Compounds CMC)) were examine for their effect on Î±-synuclein (Î±-syn) aggregation and toxicity.

Methods: The medicinal compounds were co-incubation with Î±-syn solution at three different molar ratios ( protein: compound 1:4, 1:2, and 1:1) which represent 100ÂµM, 50 ÂµM or 25ÂµM for the final concentrations of CMC compounds for 5 days at 37Â°C. The samples were then analyzed to examine fibril and oligomers formation by Th-T assay and oligomeric ELISA respectively. The results were also con-firmed by Electron Microscopy and immunoblotting techniques. We also assessed the cytotoxicity effect of CMC compounds induced by Î±-syn aggregates using MTT assay.

Results: Among the screened compounds, five compounds (CMC1, CMC4, CMC5, CMC6, and CMC12) were found strongly inhibit Î±-syn fibril formation in a dose dependent manner, while only two compounds (CMC13, and CMC14) showed an inhibitory effect on Î±-syn oligomers formation. The compounds such as CMC1, CMC3, CMC7, CMC8, CMC10, CMC11 and CMC13 failed to protect the cells from Î±-syn induced toxicity at any tested concentration, while the other CMC compounds have shown protection against ag-gregated Î±-syn at the concentration ranging from 0.5 to 5 ÂµM.

Conclusion: In this study we identified compounds that can inhibit early and late aggregate formation of Î±-syn. These compounds could represent the starting point for designing new molecules, which could be used as drugs for the treatment of Parkinsons disease.

Funding Acknowledgment: This work is funded by United Arab Emirates University-PhD program schol-arship.

Mustafa Taleb Ardah 1, Salema Begum 1, Jia-Hong Lu 2, Min Li 2 and Omar M. A. El-Agnaf 11Department of Biochemistry, Faculty of Medicine and Health Science, United Arab Emirates University, Al Ain, United Arab Emirates, 2 School of Chinese Medicine,Hong Kong Baptist University.Kowloon Tong, Hong Kong,


Purpose: In this study we have investigated the effect of fifteen Chinese medical compounds (CMC) on ï ¡-synuclein ï ¡-syn fibrillation and oligomerization.

Methods: A library of fifteen CMC compounds were screened for their effect on ï ¡-syn fibrillation using Thioflavin-T assay, while their effect on ï ¡-syn oligomerization were tested using immunoassay. Further-more, electron microscopy method was used to study the effect of the compounds on the morphology and formation of ï ¡-syn amyloid fibrils. Cell viability was also performed using MTT assay to study the toxicity of ï ¡-syn pre-incubated with CMC compounds.

Results: Of the fifteen CMC compounds, we have found only gallic acid (GA) effectively inhibited ï ¡-syn fibrillation, and at high concentration (1:4) interestingly GA showed partial inhibition of oligomers. The inhibition pattern of GA was concentration dependent as we tested three different molar ratios (1:1, 1:2, and 1:4). These results were confirmed by western blot, Th-S assay, Congo-red assay and electron microscopy. Interestingly, GA also protects the M17 cells from ï ¡-syn induced toxicity, and it was further observed that it also has the ability to disaggregate mature ï ¡-syn fibrils in a concentration dependent manner (1:2, 1:4 and 1:6), which was confirmed using Th-S, Congo-red assay and electron microscopy.

Conclusions: From our study, we have identified that GA is not limited to only inhibiting the ï ¡-syn fibrilla-tion and oligomerization; but it can also disaggregate ï ¡-syn amyloid fibrils and impart protection to cells.This compound could represent the starting point for designing new molecules, which may be used as new drugs for the treatment of Parkinsons disease.


Mustafa Taleb Ardah 1, Salema Begum 1, Jia-Hong Lu 2, Min Li 2 and Omar M. A. El-Agnaf 11Department of Biochemistry, Faculty of Medicine and Health Science, United Arab Emirates University, Al Ain, United Arab Emirates, 2 School of Chinese Medicine,Hong Kong Baptist University.Kowloon Tong, Hong Kong

Purpose: Numerous biochemical and genetic evidence suggests that the formation of ï ¡-synuclein ï ¡-syn aggregates is an important event in the development of Parkinsons disease (PD). Therefore, identifying small molecules that halt ï ¡-syn aggregation could be a promising therapeutic application for PD and re-lated diseases. In this study we screened the effect of eighteen small compounds on ï ¡-syn aggregation and toxicity.

Gallic Acid Inhibits Alpha-Synuclein Aggregation and Toxicity

Screening for Inhibitors of -Synuclein Aggregation and Toxicity





Purpose: To date there is no accepted clinical diagnostic test for Parkinsons disease (PD) based on biochemical analysis of blood or cerebrospinal fluid (CSF). Alpha-synuclein protein has been linked to the pathogenesis of PD with the discovery of mutations in the gene encoding alpha synuclein in the familial cases with early-onset PD. Lewy bodies and Lewy neuritis, which constitute the main pathological features in the brains of patients with sporadic PD and dementia with Lewy bodies, are formed by the conversion of soluble monomers of alpha-synuclein into insoluble aggregates.

Methods: Recently we have developed novel conformational antibodies specific for alpha-synuclein ag-gregates. Using these antibodies we developed ELISA assay that detects only oligomers â€œsoluble aggregatesâ€� of alpha-synuclein in human biological fluids including CSF. Using this ELISA we are screen-ing CSF samples from PD and healthy controls to measure the levels of alpha-synuclein oligomers.

Results: We report significant elevated levels of alpha-synuclein oligomers in CSF from PD compared with controls. Currently we are investigating the ratio between alpha-synuclein oligomers to total alpha-synuclein in the CSF samples.

Developing ELISA using novel conformational antibodies for detecting alpha-synuclein oligomers in human biological samples as a potential biomarker for Parkinson’s disease.

Nour MajbourMaster StudentCollege of Medicine and Health Sciences, UAE University United Arab Emirates


Methods: We tested the inhibitory effect of small compounds on ï ¡-syn fibrillation and oligomerization (early aggregates) formation by Thioflavin-S assay and immunoassay respectively. Electron microscopy and western blot were also employed to examine the effect of our compounds on the amyloid fibrils for-mation.

Results: In our current study, we found thirteen small compounds completely inhibited the amyloid fibrils formation, and five compounds were partially able to inhibit alpha-synuclein fibrils formation. However, only two of them were able to inhibit both early aggregates and late aggregates of ï ¡-syn. The inhibitory effect of these compounds was found to be dose dependent. These results were also confirmed by west-ern blotting and electron microscopy.

Conclusion: In summary, we identified compounds that can inhibit both early and late aggregate forma-tion of ï ¡-syn. These compounds could represent starting point for designing new molecules, which may contribute to develop new drugs for the treatment of Parkinsons disease.


Mustafa Taleb Ardah and Omar M.A. El-AgnafDepartment of Biochemistry, Faculty of Medicine and Health Science, United Arab Emirates University, Al Ain, United Arab Emirates,


Conclusion: These observations offer new opportunities for developing diagnostic tests for PD and as disease marker for testing therapeutic agents in clinical trials aimed at preventing or reversing the ag-gregation of alpha-synuclein.

Author Keywords: Alpha-synuclein, Parkinsons disease, Biomarkers, CSF, Conformational antibodies.

Author(s): Nour Majbour, Nishant Narayanan Vaikath, O.M.El-AgnafInstitute(s): Biochemistry, Collage of Medicine and Health Sciences, UAE University, AL Ain, United Arab Emirates

Objectives: Today, Parkinsons disease (PD) can be only diagnosed clinically, but prior to the appearance of any clinical symptoms at least 70% of neurons in the substantia nigra are lost. Interestingly, recent positron emission tomography (PET) studies have confirmed dopaminergic dysfunction in asymptomatic LRRK2 mutations carries, therefore they are an ideal population for identifying novel biomarkers for early diagnosis of PD.

Methods: We investigated total and oligomeric forms of Î± syn levels in cerebrospinal fluid (CSF) sam-ples from 33 Norwegian individuals with LRRK2 mutations: 13 patients were clinically diagnosed with PD and 20 patients were healthy, asymptomatic LRRK2 mutation carriers. In this study we also included 65 patients with sporadic PD (sPD) and 72 age-matched healthy controls.

Results: The levels of Î± syn oligomers in CSF were higher in the sPD group and the asymptomatic LRRK2 mutation carriers (p < 0.003 and p < 0.0079, respectively) as compared to the healthy control group. Oligomers/total Î± syn ratio in CSF was also significantly higher in the sPD group and the asymp-tomatic LRRK2 mutation carriers (p < 0.0001 and p < 0.0227, respectively). Interestingly, there was an inverse correlation between CSF levels of Î± syn oligomers compared to disease severity and duration. Importantly, positive correlation between the levels of CSF Î± syn oligomers and olfactory dysfunction and abnormal PET changes were observed in asymptomatic subjects carrying LRRK2 mutations.

Conclusion: Our findings provide evidence that the levels of Î±-syn oligomers combined with olfactory function assessment can be reliable biomarkers for diagnosis and early detection of PD.

Shiji Varghese áµƒ, M.M.Qureshi áµƒ, Omar M.A.EL-Agnaf áµƒ, Jan O. Aaslyáµ‡, Gunnar Bronstad Í¨áµƒ Department of Biochemistry, College of Medicine and Health Science, UAE University, Al-Ain, United Arab Emirates.áµ‡ Department of Neuroscience, Norwegian University of Science and technology, (NTNU), Trondheim, Norway.Í¨ Department of Neurology, St. Olavâ€™s Hospital, University Hospital of Trondheim, Norway.

Levels of CSF Î± synuclein oligomers correlate with olfactory and striatal dopaminergic dysfunction in asymptomatic LRRK2 mutation carriers

ShijiResearch ScientistCollege Of Medicine and Health SciencesUnited Arab Emirates



Purpose: The effects of fibrillar ï ¡-synuclein have yet to be reported using behavioural measurements in intact animals. The purpose of the current study was to determine the behavioural effects of intracer-ebroventricular (ICV) injections of fibrillar ï ¡-synuclein in the rat using a state-of-the-art operant behaviour analytical technique. And, to investigate the effect of a novel 5-aryloxypyrimidine, which has previously been shown to be protective against the toxicity induced by ICV injections of fibrillar amyloid-beta in the rat.

Method: Male Sprague-Dawley rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) operant schedule of food reinforcement. Under this schedule the rats were required to alternate responses between two levers in a computer controlled operant rat-test chamber. The pattern of operant responding from lever to lever for each discrete food reinforcer was an ascending followed by a descending lever-press requirement of 2, 6, 12, 20, 30, 40 and 56 lever responses, repeated over six cycles. This sched-ule affords insight into several parameters of memory ability, the most basic being the capacity to switch to the alternate lever after obtaining the reinforcer appropriate to the current lever press requirement and the capacity to correct an incorrect lever approach error and revert to responding on the correct lever. This generates data relative to incorrect lever approaches and incorrect lever perseverations. Following training under the ALCR schedule, subjects were fitted with a permanently indwelling cannula aimed at the lateral ventricle of the brain. Data were collected following ICV injection of fibrillar ï ¡-synuclein, and the effect of subcutaneous (SC) injection of 15 mg/kg of a novel 5-aryloxypyrimidine on ICV injected fibrillar ï ¡-synuclein-induced behavioural deficits.

Results and Conclusions: Data were analysed by one-way analysis of variance followed by Fisher’s Post-Hoc Least Significant Differences tests. SC injections of the novel 5-arylozypyrimidine or vehicle (isotonic saline) were carried out 20 minutes prior to ICV injections of ï ¡-synuclein fibrils. The ALCR test was con-ducted 2-hours post ICV injection of ï ¡-synuclein fibrils and SC drug administration. Statistically, there was a significant overall treatment effect on lever switching errors (F2,32=5.037, p=0.0125). ï ¡-synuclein fibril injected subjects exhibited significantly more lever switching errors as compared to the veh/veh injected group (p=0.0094) and the ICV ï ¡-synuclein injected group administered SC with the novel 5-ary-loxypyrimidine (p=0.0107). There was also a significant overall treatment effect on lever switching errors (F2,32=5.527, p=0.0105). ICV ï ¡-synuclein fibril injected subjects exhibited significantly more incorrect lever perseverations as compared to the veh/veh injected group (p=0.0335) and the ICV ï ¡-synuclein injected group administered SC with the novel 5-aryloxypyrimidine (p=0.0035). The results of this study show for the first time that ICV fibrillar ï ¡-synuclein injection detrimentally affects complex behaviour in an intact organism (freely moving rats), and that SC administration of a novel 5-aryloxypyrimidine alleviates the memory deterioration observed.

Memory deficits induced by intracerebroventricular injection of fibrillar -synuclein in intact rats and alleviation following subcutaneous injection of a novel 5-aryloxypyrimi-dine. Bridgeen McMahon

School of PsychologyQueen’s University, BelfastUnited Kingdom



Abstract Introduction: Alpha-synuclein (AS) aggregation is thought to constitute one of the key events preceding Lewy body formation in synucleinopathies such as Parkinsons disease (PD) and dementia with Lewy bodies (DLB). Previous studies have proposed several processes potentially leading to AS aggre-gation further contributing to disease progression; including point mutation and posttranslational modi-fications, such as phosphorylation, oxidation, glycosylation, and sumoylation. Although AS alterations and modifications have been proposed to be responsible for early aggregation steps, the mechanisms underlying these events remain unclear. Moreover, AS is found in four alternative splicing isoforms and the different primary structures of these four AS proteins result in aggregation propensity.

Methods: Alpha-synuclein isoforms were directly in-solution digested or separated by 1- and 2-DE after which proteins were digested in-gel with trypsin and chymotrypsin or first electro-eluted using Protea-Biosciencesâ€™ (Morgantown, WV) gel protein recovery (GPR) system. Bottom-up analysis was carried out on an LTQ-Orbitrap or SYNAPT using: 1) direct infusion with PAcIFIC acquiring tandem mass spectra on every m/z from 300-2000 and 2) DDA C18-HPLC DDA (Scherl et al. JASMS 2008). Top-down experi-ments were carried out on a ThermoFisher LTQ-Orbitrap and Waters SYNAPT HDMS by either infusion or C4-HPLC data-dependent analysis (DDA) PTM discovery analysis was as reported (Singh et al. Analytical Chemistry 2008) and top-down analysis used PIITA to match observed protein sequence tags to gene sequence.

Conclusion: Comprehensive analysis of a biomarker of Parkinson’s disease, alpha-synuclein, is dem-onstrated by 2-dimentional immunoblot, top-down and bottom-up approaches. More than fifteen alpha-synuclein isotypes were resolved by 2D gel and identified by MS. PTMs analysis demonstrated that alpha-synuclein is acetylated in human blood. We believe combined with bioinformatics tools and different proteomic strategy such as middle-down approach and electron-capture dissociation (ECD) and electron-transfer disassociation (ETD) we can improve the PTM identification, which is an aspect that we are cur-rently investigating.

Top-Down and Bottom-Up Strategy for Characterization of Alpha-synuclein Isoform in Parkinsons Disease

Catherine PanUniversity of WashingtonUnited States



Abstract Background: Over the past years, different compounds have been isolated from Germander (Teucrium polium) of which the main groups are terpenoids and flavonoids. Anticholinesterase effects of Teucrium polium in the nervous system are less studied. On the other hand numerous clinical and experimental studies of postmenopausal women and ovariectomized (OVX) animals testify about neuro-degenerative alterations in various structures of the brain, associated with mental function (in particular, hippocamp and basal nucleus of Meynert). With the purpose of getting ecologically clean product, pro-grammed chemical compound and productivit Teucrium polium has been included into growing culture. Expediency of growing the plant in hydroponic condition is established.

Methods: According to electrophysiological data in neurons of basal nucleus of Meynert under high fre-quency stimulation of hippocamp causes excitation and inhibition responses by equal quantity.

Results: After 6, 8 weeks of bilateral OVX in placebo control group about deficiency of neurotransmit-ters and damage of synaptic transmission testify sharp increase in number of areactive neuronal units. I/m injection of Teucrium polium (20 mg/kg within 3 weeks) starting from 3th week after OVX prevents neurodegenerative alterations exhibited in placebo-control on the 6, 8th weeks (according to criteria of expression of excitatory and inhibitory responses, correlation of reactive and areactive units). Thees data suggest the anticholinesterase activity of Teucrium polium and abilities its bioactive compounds to modu-late some neurotransmitter systems.

Conclusion: Thus, hydroponic Teucrium polium is advisable to recommend for approval in clinical prac-tice to postmenopausal women for prevention of mental disturbances.

Top-Down and Bottom-Up Strategy for Characterization of Alpha-synuclein Isoform in Parkinsons Disease

Karen SimonyanPhD, Orbeli Institute of Physiology, Republic of ArmeniaArmenia



Kinases are regulating many cellular functions and mapping the importance of specific kinases activated during disease progress may reveal mechanisms as well as potential targets for intervention.

a-synuclein is a key player in many hypotheses of the cytotoxic routes to neurodegeneration and the phosphorylation of Ser-129 on a-synuclein is a hallmark of pathological deposits in brains affected by Parkinson’s disease, Dementia with Lewy bodies and Multiple system atrophy. Experimental evidences indicate a pathogenic role of the a-synuclein ser-129 phosphorylation in cellular degeneration, although this is controversial.

We present data from a high content screening platform based on a-synuclein aggregation dependent cell death in an oligodendroglial cell model. This provides a strong tool for testing multiple compounds in an automatized and unbiased manner. We have conducted a screen of 160 small molecule kinase inhibitors with known mechanism of action. The cell model is based on p25 induced a-synuclein dependent degen-eration measured by a morphological collapse of the cytoskeleton in an oligodendroglial cell line, OLN-93. We report that modulating signaling pathways controlled by kinase activity can reduce the ongoing degen-eration. 13 different primary targets were revealed as potential targets of intervention with approximately 50-90% rescuing effect. The kinases PLK2, PLK3 and CKII were further validated for their action as cel-lular kinases i) phosphorylating Ser-129 on a-synuclein and ii) mediating cytotoxic signalling.

Louise Buur Vesterager1, Poul Henning Jensen2, Karina Fog11Department for Neurodegeneration 1, H. Lundbeck, DK-2500 Valby, Denmark2Department for Biomedicine, Aarhus University, DK-8000 Aarhus, Denmark

Image based high content screening for kinase pathways involved in a-synuclein aggregation dependent cell death.

Louise Buur VesteragerResearch ScientistNuerodegeneration1Denmark



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Confernce Book 2013

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