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Prion Disease Transmissible spongiform encephalopathy (TSE)

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Presentation on theme: "Prion Disease Transmissible spongiform encephalopathy (TSE)"— Presentation transcript:

1 Prion Disease Transmissible spongiform encephalopathy (TSE)
Neurodegeneration, vacuolation, and deposition of abnormal prion protein Cross-species infectivity Attributable to a proteinaceous infectious agent PrPC Alpha-helical form PrPSc Beta-sheet disease associated form

2 Hosts ‘Natural’ disease: BSE affected species:
Man: Creutzfeldt-Jakob Disease (CJD) Deer: Chronic Wasting Disease Sheep/ Goats: Scrapie BSE affected species: Cattle: BSE Man: vCJD Domestic & wild cats: FSE Greater kudu, nyala, Arabian oryx, scimitar horned oryx, eland, gemsbok, bison, ankole, tiger, cheetah, ocelot, puma.

3 Human Prion Disease Sporadic Familial / Genetic Acquired
Sporadic CJD (sCJD) Sporadic Fatal Insomnia (sFI) Familial / Genetic fCJD Gerstmann Sträussler Scheinker (GSS) Fatal Familial Insomnia (FFI) Acquired Iatrogenic CJD (iCJD) Variant CJD (vCJD) from BSE Variant CJD from blood transfusion Kuru (cannibalism – Papua New Guinea)


5 Prion Protein: Western Blot

6 Prion Protein Gene (PRNP)
M129V 1 254

7 Codon 129 Genotype & CJD Sporadic CJD (n=832) Variant (n=146)
Iatrogenic (n=128) MM 71% 100% 57% MV 13% 0% 20% VV 16% 23% Normal Pop (n=406) 40% 48% 11% UK sCJD: Alperovitch, et al. (1999) Lancet, 353, iCJD: Brown, P. et al. (2000) Neurology, 55, UK Pop: Nurmi, M. H., Bishop, M., et al. (2003) Acta Neurol Scand, 108,

8 Codon 129 Genotype: Other Diseases
PRNP M129V homozygosity in multiple system atrophy vs. Parkinson's disease (Clin Auton Res Feb;18(1):13-9) Prion protein gene M129 allele is a risk factor for Alzheimer's disease. (J Neural Transm Nov;113(11): ) 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 Jun 21;421(1):1-4) Prion protein gene codon 129 modulates clinical course of neurological Wilson disease (Neuroreport Apr 3;17(5):549-52) Prion protein codon 129 genotype prevalence is altered in primary progressive aphasia (Ann Neurol Dec;58(6):858-64)

9 Transgenic Mice In Human Prion Disease Research
PrP knockout mice PrP over-expressing mice Mouse / Human PrP chimeras Human PrP over-expressing mice Human single copy PRNP mice Human mutation models in mouse Prnp Gene targeted mice

10 ‘Human’ Transgenic Mice
Human prion protein transgene (Codon 129: M or V) Wild-type HuMM HuMV HuVV - HuMM (HuMV) HuVV Mouse prion gene replaced by transgene

11 Variant CJD (MM) Transmission Codon 129 Affecting ‘Susceptibility’
HuMM HuMV HuVV Overall Score ------ Mice Positive For: CLINICAL TSE TSE VACUOLATION ABNORMAL PrP BSE Inoculation 12/16 x2 x6 x12 0/18 11/15 x1 x11 0/23 1/15 x0 0/22 Bishop et al Lancet Neurology 2006; 5(5): p

12 Variant CJD (MM) vs. Blood Transfusion vCJD
HuMM HuMV HuVV Overall Score ------ Mice Positive For: CLINICAL TSE TSE VACUOLATION ABNORMAL PrP 12/16 13/14 x x1 x x8 x x13 11/ /17 x x2 x x0 x x8 1/ /17 x x0 x x1 Bishop et al Lancet Neurology 2006; 5(5): p Bishop, et al (2008) PLoS ONE, 3, e2878

13 Variant CJD (MM) Inoculation Codon 129 Affecting Progression of PrP Deposition
HuMM – 500 days HuMM – 700 days HuMV – 600 days HuMV – 700 days

14 Sporadic CJD Inoculation
Six typical cases of sCJD defined by codon 129 and PrPSc type: MM1 & MM2 MV1 & MV2 VV1 & VV2 HuMM HuMV HuVV Intra-cerebral Analysis Incubation period to clinical TSE TSE vacuolation scoring PrPSc typing by Western blot PrPSc detection by immunocytochemistry

15 Benefits of Model Comparative analysis of effect of codon 129 genotype between three genetically identical mouse lines Model of genotype susceptibility and pathology of vCJD Bioassay system for distinguishing human prion disease strains – emerging novel diseases Model of neurodegenerative disease

16 Acknowledgements The Roslin Institute, Neuropathogenesis Division
Mouse Genetics Prof Jean Manson H Baybutt L Blackford Mouse Facility Irene McConnell V Thomson S Shillinglaw R Greenan Pathology Anne Coghill A Boyle G McGregor S Mack 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

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