Prion DiseasePrion Disease Transmissible spongiform encephalopathy (TSE)Transmissible spongiform encephalopathy (TSE) Neurodegeneration, vacuolation, and deposition of Neurodegeneration, vacuolation, and deposition of

abnormal prion proteinabnormal prion protein Cross-species infectivityCross-species infectivity Attributable to a proteinaceous infectious agentAttributable to a proteinaceous infectious agent

PrPC

Alpha-helical form

PrPSc

Beta-sheet disease associated form

HostsHosts‘‘Natural’ disease:Natural’ disease:

Man: Creutzfeldt-Jakob Disease (CJD)Man: Creutzfeldt-Jakob Disease (CJD) Deer: Chronic Wasting Disease Deer: Chronic Wasting Disease Sheep/ Goats: ScrapieSheep/ Goats: Scrapie

BSE affected species: BSE affected species: Cattle: BSE Cattle: BSE Man: vCJDMan: vCJD Domestic & wild cats: FSEDomestic & wild cats: FSE Greater kudu, nyala, Arabian oryx, scimitar horned Greater kudu, nyala, Arabian oryx, scimitar horned

oryx, eland, gemsbok, bison, ankole, tiger, cheetah, oryx, eland, gemsbok, bison, ankole, tiger, cheetah, ocelot, puma.ocelot, puma.

Human Prion DiseaseHuman Prion DiseaseSporadicSporadic

Sporadic CJD (sCJD)Sporadic CJD (sCJD) Sporadic Fatal Insomnia (sFI)Sporadic Fatal Insomnia (sFI)

Familial / GeneticFamilial / Genetic fCJDfCJD Gerstmann Sträussler Scheinker Gerstmann Sträussler Scheinker (GSS)(GSS) Fatal Familial Insomnia (FFI)Fatal Familial Insomnia (FFI)

AcquiredAcquired Iatrogenic CJD (iCJD)Iatrogenic CJD (iCJD) Variant CJD (vCJD) from BSEVariant CJD (vCJD) from BSE Variant CJD from blood transfusionVariant CJD from blood transfusion Kuru (cannibalism – Papua New Guinea)Kuru (cannibalism – Papua New Guinea)

Prion Protein: Western BlotPrion Protein: Western Blot

Prion Protein Gene (Prion Protein Gene (PRNPPRNP))

M129V

1 254

Codon 129 Genotype & Codon 129 Genotype & CJDCJD

Sporadic

CJD

(n=832)

Variant CJD

(n=146)

Iatrogenic CJD

(n=128)

MM 71% 100% 57%

MV 13% 0% 20%

VV 16% 0% 23%

Normal Pop

(n=406)

40%

48%

11%

UK

sCJD: Alperovitch, et al. (1999) Lancet, 353, 1673-4iCJD: Brown, P. et al. (2000) Neurology, 55, 1075-81UK Pop: Nurmi, M. H., Bishop, M., et al. (2003) Acta Neurol Scand, 108, 374-378

Codon 129 Genotype: Other Codon 129 Genotype: Other DiseasesDiseases

• PRNP M129V homozygosity in multiple system atrophy vs.

Parkinson's disease (Clin Auton Res. 2008 Feb;18(1):13-9)

• Prion protein gene M129 allele is a risk factor for Alzheimer's disease. (J Neural Transm. 2006 Nov;113(11):1747-51)

• Absence of association between codon 129 and 219 polymorphisms of the prion protein gene and vascular dementia (Dement Geriatr Cogn Disord. 2007;24(2):86-90)

• Association between the M129V variant allele of PRNP gene and mild temporal lobe epilepsy in women (Neurosci Lett. 2007 Jun 21;421(1):1-4)

• Prion protein gene codon 129 modulates clinical course of neurological Wilson disease (Neuroreport. 2006 Apr 3;17(5):549-52)

• Prion protein codon 129 genotype prevalence is altered in primary progressive aphasia (Ann Neurol. 2005 Dec;58(6):858-64)

Transgenic Mice In Human Prion Transgenic Mice In Human Prion Disease ResearchDisease Research

PrP knockout micePrP knockout mice

PrP over-expressing micePrP over-expressing mice

Mouse / Human PrP chimerasMouse / Human PrP chimeras

Human PrP over-expressing miceHuman PrP over-expressing mice

Human single copy PRNP miceHuman single copy PRNP mice

Human mutation models in mouse Prnp Human mutation models in mouse Prnp

Gene targeted mice Gene targeted mice

Human prion protein transgene (Codon 129: M or V)

Mouse prion gene replaced by transgene

HuMM HuVV(HuMV)W

ild-

typ

e- H

uM

M- H

uM

V- H

uV

V-

‘‘Human’ Transgenic MiceHuman’ Transgenic Mice

Variant CJD (MM) TransmissionVariant CJD (MM) TransmissionCodon 129 Affecting Codon 129 Affecting

‘Susceptibility’‘Susceptibility’HuMMHuMM HuMVHuMV HuVVHuVV

Overall ScoreOverall Score

------------Mice Positive For:Mice Positive For:

CLINICAL TSECLINICAL TSE

TSE TSE VACUOLATIONVACUOLATION

ABNORMAL PrPABNORMAL PrP

------------BSE InoculationBSE Inoculation

12/1612/16

------------

x2x2

x6x6

x12x12

------------0/180/18

11/1511/15

------------

x1x1

x1x1

x11x11

------------0/230/23

1/151/15

------------

x0x0

x1x1

x1x1

------------0/220/22

Bishop et al Lancet Neurology 2006; 5(5): p.393-398

Variant CJD (MM)Variant CJD (MM)vs. vs. Blood Transfusion vCJDBlood Transfusion vCJD

HuMMHuMM HuMVHuMV HuVVHuVV

Overall ScoreOverall Score

------------Mice Positive For:Mice Positive For:

CLINICAL TSECLINICAL TSE

TSE TSE VACUOLATIONVACUOLATION

ABNORMAL PrPABNORMAL PrP

12/16 12/16 13/1413/14

------------

x2 x2 x1x1

x6 x6 x8x8

x12 x12 x13 x13

11/15 11/15 8/178/17

------------

x1 x1 x2x2

x1 x1 x0x0

x11 x11 x8x8

1/15 1/15 1/171/17

------------

x0 x0 x0x0

x1 x1 x0x0

x1 x1 x1x1

Bishop et al Lancet Neurology 2006; 5(5): p.393-398Bishop, et al (2008) PLoS ONE, 3, e2878

HuMM – 700 daysHuMM – 500 days

HuMV – 700 daysHuMV – 600 days

Variant CJD (MM) InoculationVariant CJD (MM) InoculationCodon 129 Affecting Progression of PrP Codon 129 Affecting Progression of PrP

DepositionDeposition

Sporadic CJD InoculationSporadic CJD InoculationSix typical cases of sCJD defined by codon 129 and PrPSc type:

MM1 & MM2MV1 & MV2VV1 & VV2

HuMMHuMVHuVV

AnalysisIncubation period to clinical TSETSE vacuolation scoringPrPSc typing by Western blot PrPSc detection by immunocytochemistry

Intra-cerebral

Benefits of ModelBenefits of ModelComparative analysis of effect of codon Comparative analysis of effect of codon 129 genotype between three genetically 129 genotype between three genetically identical mouse linesidentical mouse linesModel of genotype susceptibility and Model of genotype susceptibility and pathology of vCJDpathology of vCJDBioassay system for distinguishing human Bioassay system for distinguishing human prion disease strains – emerging novel prion disease strains – emerging novel diseasesdiseasesModel of neurodegenerative diseaseModel of neurodegenerative disease

AcknowledgementsAcknowledgements

Mouse Genetics

Prof Jean Manson

H Baybutt

L Blackford

Mouse Facility

Irene McConnell

V Thomson

S Shillinglaw

R Greenan

The Roslin Institute, Neuropathogenesis Division

UK National CJD Surveillance Unit

Prof Bob Will M Le Grice

Prof James Ironside S Lowrie

L McCardle D Ritchie

C-A McKenzie A Peden

M Head H Yull

Pathology

Anne Coghill

A Boyle

G McGregor

S Mack