Prion Diseases

J. Spencer Schwarz

Spongiform Encephalopathies

• Scrapie in sheep• BSE in Cattle• Kuru, GSS, FII, Human BSE in Humans

Loss of motor control, dementia,paralysis wasting and death

Non-inflammatory lesions, vacuoles,amyloid protein deposits andastrogliosis

The Prion Hypothesis

Prions are transmissible particles that are devoid of nucleic acid andseem to be composed exclusively of a modified protein (PrPsc)

-Prusiner 1966

Lack of recombinant infectionmaterial

No characterization of infectiousparticle

Specific activity of purifiedagent extremely low.

Infection without proteaseresistant PrPsc has been found

PrPc and PrPsc

Infection

Infection

Infection

Infection

Finding a Cure

• Pathology Undefined

• No structural Characterization ofPrPsc

• No Characterization of Interaction

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Prion Spinoffs

• The prion pathway has elucidated a whole new paradigmfor non-mendelian heredity

• PSI+ and URE3 use prion pathway, are essential to yeast• Isoforms “infect” daughter cells and cause conformation

change in endogenous Protein

References

Chien, Emerging Principles of Conformation-Based Prion InheritanceAnnual Review of Biochemistry, 2004, 73:617-656

Mabbot, Prions and their Lethal Journey to the BrainNature Reviews, 2006, 4:201-211

Barducci, Metadynamics Simulation of Prion Protein: B-structure stability and the EarlyStages of MisfoldingJournal of the American Chemical Society, 2006, 128: 2705-2710

Cox, Prion Disease: Exponential Growth Requires Membrane BindingBiophysics Journal, 2006, E-published ahead of print

Waldman, Regional Brain Metabolite abnormalities in inherited prion disease andasymptomatic gene carriers demonstrated by quanitative proton magentic resonancespectroscopyNueroradiology, 2006, Epub ahead of Print

Prusiner, nobel prize lecture,nobelprize.org, 2006 (1966)

Microbiology at Leicester, Prion Diseaseshttp://www-micro.msb.le.ac.uk/3035/prions.html, 2001