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