Prion Disease

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Prion Disease

• Transmissible spongiform encephalopathy (TSE)
• Neurodegeneration, vacuolation, and deposition of
  abnormal prion protein
• Cross-species infectivity
• Attributable to a proteinaceous infectious agent

PrPSc Beta-sheet disease associated form
PrPC Alpha-helical form
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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.

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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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(No Transcript)
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Prion Protein Western Blot
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Prion Protein Gene (PRNP)
M129V
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254
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Codon 129 Genotype CJD
sCJD Alperovitch, et al. (1999) Lancet, 353,
1673-4 iCJD Brown, P. et al. (2000) Neurology,
55, 1075-81 UK Pop Nurmi, M. H., Bishop, M., et
al. (2003) Acta Neurol Scand, 108, 374-378
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Codon 129 Genotype Other Diseases

• PRNP M129V homozygosity in multiple system
  atrophy vs. Parkinson's disease (Clin Auton Res.
  2008 Feb18(1)13-9)
• Prion protein gene M129 allele is a risk factor
  for Alzheimer's disease. (J Neural Transm. 2006
  Nov113(11)1747-51)
• Absence of association between codon 129 and 219
  polymorphisms of the prion protein gene and
  vascular dementia (Dement Geriatr Cogn Disord.
  200724(2)86-90)
• Association between the M129V variant allele of
  PRNP gene and mild temporal lobe epilepsy in
  women (Neurosci Lett. 2007 Jun 21421(1)1-4)
• Prion protein gene codon 129 modulates clinical
  course of neurological Wilson disease
  (Neuroreport. 2006 Apr 317(5)549-52)
• Prion protein codon 129 genotype prevalence is
  altered in primary progressive aphasia (Ann
  Neurol. 2005 Dec58(6)858-64)

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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

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Human Transgenic Mice
Human prion protein transgene (Codon 129 M or
V)
Wild-type - HuMM - HuMV - HuVV -
HuVV
(HuMV)
HuMM
Mouse prion gene replaced by transgene
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Variant CJD (MM) TransmissionCodon 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 x1 x11 ------ 0/23 1/15 ------ x0 x1 x1 ------ 0/22
Bishop et al Lancet Neurology 2006 5(5)
p.393-398
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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 ------ x2 x1 x6 x8 x12 x13 11/15 8/17 ------ x1 x2 x1 x0 x11 x8 1/15 1/17 ------ x0 x0 x1 x0 x1 x1
Bishop et al Lancet Neurology 2006 5(5)
p.393-398 Bishop, et al (2008) PLoS ONE, 3, e2878
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Variant CJD (MM) InoculationCodon 129 Affecting
Progression of PrP Deposition
HuMM 700 days
HuMM 500 days
HuMV 700 days
HuMV 600 days
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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
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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

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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