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Prion Disease  Transmissible spongiform encephalopathy (TSE)  Neurodegeneration, vacuolation, and deposition of abnormal prion protein  Cross-species.

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Presentation on theme: "Prion Disease  Transmissible spongiform encephalopathy (TSE)  Neurodegeneration, vacuolation, and deposition of abnormal prion protein  Cross-species."— 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 PrP C Alpha-helical form PrP Sc Beta-sheet disease associated form

2 Hosts  ‘Natural’ disease:  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  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)

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5 Prion Protein: Western Blot

6 Prion Protein Gene (PRNP) M129V 1 254

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

11 Variant CJD (MM) Transmission Codon 129 Affecting ‘Susceptibility’ HuMMHuMVHuVV Overall Score Mice Positive For: CLINICAL TSE TSE VACUOLATION ABNORMAL PrP BSE Inoculation 12/ x2x6x /1811/ x1x1x /231/ x0x1x /22 Bishop et al Lancet Neurology 2006; 5(5): p

12 Variant CJD (MM) vs. Blood Transfusion vCJD HuMMHuMVHuVV Overall Score Mice Positive For: CLINICAL TSE TSE VACUOLATION ABNORMAL PrP 12/16 13/ x2 x1 x6 x8 x12 x13 11/15 8/ x1 x2 x1 x0 x11 x8 1/15 1/ x0 x0 x1 x0 x1 x1 Bishop et al Lancet Neurology 2006; 5(5): p Bishop, et al (2008) PLoS ONE, 3, e2878

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

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

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 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


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