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Prion Disease

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Title: Prion Disease


1
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
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)

4
(No Transcript)
5
Prion Protein Western Blot
6
Prion Protein Gene (PRNP)
M129V
1
254
7
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
8
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)

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 -
HuVV
(HuMV)
HuMM
Mouse prion gene replaced by transgene
11
Variant CJD (MM) TransmissionCodon 129 Affecting
Susceptibility
Bishop et al Lancet Neurology 2006 5(5)
p.393-398
12
Variant CJD (MM)vs. Blood Transfusion vCJD
Bishop et al Lancet Neurology 2006 5(5)
p.393-398 Bishop, et al (2008) PLoS ONE, 3, e2878
13
Variant CJD (MM) InoculationCodon 129 Affecting
Progression of PrP Deposition
HuMM 700 days
HuMM 500 days
HuMV 700 days
HuMV 600 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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