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Prion Diseases
J. Spencer Schwarz
Spongiform Encephalopathies
• Scrapie in sheep• BSE in Cattle• Kuru, GSS, FII, Human BSE in Humans
Loss of motor control, dementia,paralysis wasting and death
Non-inflammatory lesions, vacuoles,amyloid protein deposits andastrogliosis
The Prion Hypothesis
Prions are transmissible particles that are devoid of nucleic acid andseem to be composed exclusively of a modified protein (PrPsc)
-Prusiner 1966
Lack of recombinant infectionmaterial
No characterization of infectiousparticle
Specific activity of purifiedagent extremely low.
Infection without proteaseresistant PrPsc has been found
PrPc and PrPsc
Infection
Infection
Infection
Infection
Finding a Cure
• Pathology Undefined
• No structural Characterization ofPrPsc
• No Characterization of Interaction
?
?
?
Prion Spinoffs
• The prion pathway has elucidated a whole new paradigmfor non-mendelian heredity
• PSI+ and URE3 use prion pathway, are essential to yeast• Isoforms “infect” daughter cells and cause conformation
change in endogenous Protein
References
Chien, Emerging Principles of Conformation-Based Prion InheritanceAnnual Review of Biochemistry, 2004, 73:617-656
Mabbot, Prions and their Lethal Journey to the BrainNature Reviews, 2006, 4:201-211
Barducci, Metadynamics Simulation of Prion Protein: B-structure stability and the EarlyStages of MisfoldingJournal of the American Chemical Society, 2006, 128: 2705-2710
Cox, Prion Disease: Exponential Growth Requires Membrane BindingBiophysics Journal, 2006, E-published ahead of print
Waldman, Regional Brain Metabolite abnormalities in inherited prion disease andasymptomatic gene carriers demonstrated by quanitative proton magentic resonancespectroscopyNueroradiology, 2006, Epub ahead of Print
Prusiner, nobel prize lecture,nobelprize.org, 2006 (1966)
Microbiology at Leicester, Prion Diseaseshttp://www-micro.msb.le.ac.uk/3035/prions.html, 2001
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