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Prion DiseasePrion Disease Transmissible spongiform encephalopathy (TSE)Transmissible spongiform encephalopathy (TSE) Neurodegeneration, vacuolation, and deposition of Neurodegeneration, vacuolation, and deposition of
abnormal prion proteinabnormal prion protein Cross-species infectivityCross-species infectivity Attributable to a proteinaceous infectious agentAttributable to a proteinaceous infectious agent
PrPC
Alpha-helical form
PrPSc
Beta-sheet disease associated form
HostsHosts‘‘Natural’ disease:Natural’ disease:
Man: Creutzfeldt-Jakob Disease (CJD)Man: Creutzfeldt-Jakob Disease (CJD) Deer: Chronic Wasting Disease Deer: Chronic Wasting Disease Sheep/ Goats: ScrapieSheep/ Goats: Scrapie
BSE affected species: BSE affected species: Cattle: BSE Cattle: BSE Man: vCJDMan: vCJD Domestic & wild cats: FSEDomestic & wild cats: FSE Greater kudu, nyala, Arabian oryx, scimitar horned Greater kudu, nyala, Arabian oryx, scimitar horned
oryx, eland, gemsbok, bison, ankole, tiger, cheetah, oryx, eland, gemsbok, bison, ankole, tiger, cheetah, ocelot, puma.ocelot, puma.
Human Prion DiseaseHuman Prion DiseaseSporadicSporadic
Sporadic CJD (sCJD)Sporadic CJD (sCJD) Sporadic Fatal Insomnia (sFI)Sporadic Fatal Insomnia (sFI)
Familial / GeneticFamilial / Genetic fCJDfCJD Gerstmann Sträussler Scheinker Gerstmann Sträussler Scheinker (GSS)(GSS) Fatal Familial Insomnia (FFI)Fatal Familial Insomnia (FFI)
AcquiredAcquired Iatrogenic CJD (iCJD)Iatrogenic CJD (iCJD) Variant CJD (vCJD) from BSEVariant CJD (vCJD) from BSE Variant CJD from blood transfusionVariant CJD from blood transfusion Kuru (cannibalism – Papua New Guinea)Kuru (cannibalism – Papua New Guinea)
Codon 129 Genotype & Codon 129 Genotype & CJDCJD
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, 1673-4iCJD: Brown, P. et al. (2000) Neurology, 55, 1075-81UK Pop: Nurmi, M. H., Bishop, M., et al. (2003) Acta Neurol Scand, 108, 374-378
Codon 129 Genotype: Other Codon 129 Genotype: Other DiseasesDiseases
• PRNP M129V homozygosity in multiple system atrophy vs.
Parkinson's disease (Clin Auton Res. 2008 Feb;18(1):13-9)
• Prion protein gene M129 allele is a risk factor for Alzheimer's disease. (J Neural Transm. 2006 Nov;113(11):1747-51)
• 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. 2007 Jun 21;421(1):1-4)
• Prion protein gene codon 129 modulates clinical course of neurological Wilson disease (Neuroreport. 2006 Apr 3;17(5):549-52)
• Prion protein codon 129 genotype prevalence is altered in primary progressive aphasia (Ann Neurol. 2005 Dec;58(6):858-64)
Transgenic Mice In Human Prion Transgenic Mice In Human Prion Disease ResearchDisease Research
PrP knockout micePrP knockout mice
PrP over-expressing micePrP over-expressing mice
Mouse / Human PrP chimerasMouse / Human PrP chimeras
Human PrP over-expressing miceHuman PrP over-expressing mice
Human single copy PRNP miceHuman single copy PRNP mice
Human mutation models in mouse Prnp Human mutation models in mouse Prnp
Gene targeted mice Gene targeted mice
Human prion protein transgene (Codon 129: M or V)
Mouse prion gene replaced by transgene
HuMM HuVV(HuMV)W
ild-
typ
e- H
uM
M- H
uM
V- H
uV
V-
‘‘Human’ Transgenic MiceHuman’ Transgenic Mice
Variant CJD (MM) TransmissionVariant CJD (MM) TransmissionCodon 129 Affecting Codon 129 Affecting
‘Susceptibility’‘Susceptibility’HuMMHuMM HuMVHuMV HuVVHuVV
Overall ScoreOverall Score
------------Mice Positive For:Mice Positive For:
CLINICAL TSECLINICAL TSE
TSE TSE VACUOLATIONVACUOLATION
ABNORMAL PrPABNORMAL PrP
------------BSE InoculationBSE Inoculation
12/1612/16
------------
x2x2
x6x6
x12x12
------------0/180/18
11/1511/15
------------
x1x1
x1x1
x11x11
------------0/230/23
1/151/15
------------
x0x0
x1x1
x1x1
------------0/220/22
Bishop et al Lancet Neurology 2006; 5(5): p.393-398
Variant CJD (MM)Variant CJD (MM)vs. vs. Blood Transfusion vCJDBlood Transfusion vCJD
HuMMHuMM HuMVHuMV HuVVHuVV
Overall ScoreOverall Score
------------Mice Positive For:Mice Positive For:
CLINICAL TSECLINICAL TSE
TSE TSE VACUOLATIONVACUOLATION
ABNORMAL PrPABNORMAL PrP
12/16 12/16 13/1413/14
------------
x2 x2 x1x1
x6 x6 x8x8
x12 x12 x13 x13
11/15 11/15 8/178/17
------------
x1 x1 x2x2
x1 x1 x0x0
x11 x11 x8x8
1/15 1/15 1/171/17
------------
x0 x0 x0x0
x1 x1 x0x0
x1 x1 x1x1
Bishop et al Lancet Neurology 2006; 5(5): p.393-398Bishop, et al (2008) PLoS ONE, 3, e2878
HuMM – 700 daysHuMM – 500 days
HuMV – 700 daysHuMV – 600 days
Variant CJD (MM) InoculationVariant CJD (MM) InoculationCodon 129 Affecting Progression of PrP Codon 129 Affecting Progression of PrP
DepositionDeposition
Sporadic CJD InoculationSporadic CJD InoculationSix typical cases of sCJD defined by codon 129 and PrPSc type:
MM1 & MM2MV1 & MV2VV1 & VV2
HuMMHuMVHuVV
AnalysisIncubation period to clinical TSETSE vacuolation scoringPrPSc typing by Western blot PrPSc detection by immunocytochemistry
Intra-cerebral
Benefits of ModelBenefits of ModelComparative analysis of effect of codon Comparative analysis of effect of codon 129 genotype between three genetically 129 genotype between three genetically identical mouse linesidentical mouse linesModel of genotype susceptibility and Model of genotype susceptibility and pathology of vCJDpathology of vCJDBioassay system for distinguishing human Bioassay system for distinguishing human prion disease strains – emerging novel prion disease strains – emerging novel diseasesdiseasesModel of neurodegenerative diseaseModel of neurodegenerative disease
AcknowledgementsAcknowledgements
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