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malattie prioniche

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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.

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.

Published in: Technology, Health & Medicine

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  • 1. Prion Disease
    • Transmissible spongiform encephalopathy (TSE)
    • Neurodegeneration, vacuolation, and deposition of abnormal prion protein
    • Cross-species infectivity
    • Attributable to a proteinaceous infectious agent
    PrP C Alpha-helical form PrP Sc Beta-sheet disease associated 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.  
  • 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 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
  • 8. Codon 129 Genotype: Other Diseases
    • 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)
  • 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 prion protein transgene (Codon 129: M or V) Mouse prion gene replaced by transgene HuMM HuVV (HuMV) Wild-type - HuMM - HuMV - HuVV - ‘ Human’ Transgenic Mice
  • 11. Variant CJD (MM) Transmission Codon 129 Affecting ‘Susceptibility’ Bishop et al Lancet Neurology 2006; 5 (5): p.393-398 Overall Score ------ Mice Positive For: CLINICAL TSE TSE VACUOLATION ABNORMAL PrP ------ BSE Inoculation 1/15 ------ x0 x1 x1 ------ 0/22 11/15 ------ x1 x1 x11 ------ 0/23 12/16 ------ x2 x6 x12 ------ 0/18 HuVV HuMV HuMM
  • 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 Overall Score ------ Mice Positive For: CLINICAL TSE TSE VACUOLATION ABNORMAL PrP 1/15 1/17 ------ x0 x0 x1 x0 x1 x1 11/15 8/17 ------ x1 x2 x1 x0 x11 x8 12/16 13/14 ------ x2 x1 x6 x8 x12 x13 HuVV HuMV HuMM
  • 13. HuMM – 700 days HuMM – 500 days HuMV – 700 days HuMV – 600 days Variant CJD (MM) Inoculation Codon 129 Affecting Progression of PrP Deposition
  • 14. Sporadic CJD Inoculation Six typical cases of sCJD defined by codon 129 and PrP Sc type: MM1 & MM2 MV1 & MV2 VV1 & VV2 HuMM HuMV HuVV Analysis Incubation period to clinical TSE TSE vacuolation scoring PrP Sc typing by Western blot PrP Sc detection by immunocytochemistry Intra-cerebral
  • 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
    • 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