Prion Disease Prion Disease Transmissible spongiform encephalopathy Transmissible spongiform encephalopathy (TSE) (TSE) Neurodegeneration, vacuolation, and Neurodegeneration, vacuolation, and deposition of abnormal prion protein deposition of abnormal prion protein Cross-species infectivity Cross-species infectivity Attributable to a proteinaceous infectious Attributable to a proteinaceous infectious agent agent PrP C Alpha- helical form PrP Sc Beta- sheet disease associat ed form
presentazione tratta dal sito del Centre for clinical Brain Science (http://www.ccbs.ed.ac.uk/default.asp) sulla malattia prionica e sul modello murino transgenico.
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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
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)
Prion Protein: Western BlotPrion Protein: Western Blot
Prion Protein Gene (Prion Protein Gene (PRNPPRNP))
M129V
1 254
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
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