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Infectivity associated to PrP aggregate fractions - SE2012

Description
Neurodegenerative diseases such as Alzheimer's, Parkinson's and transmissible spongiform encephalopathies (TSE) are characterized by abnormal deposits of amyloid proteins in the central nervous system of the affected individuals. In TSEs, deposits are enriched in an abnormal protease-resistant protein (PrPres), resulting from the conversion of a normal endogen protease-sensitive protein, the Prion protein (PrPsen). PrPres is currently the only known specific marker of TSE. According to the ’Prion’ hypothesis abnormal PrP itself would be the infectious agent. However discrepancies exist between the presence of PrPres deposits and TSE infectivity: presence of infectivity without detectable levels of PrPres have been reported. In that context questions have arisen to know if PrPres aggregates or smaller oligomers (with low protease resistance) are the primary causes of the diseases, and vectors of infectivity.
In designing strategies for TSEs infections diagnosis but also strategies for therapeutics, identifying PrP species that would be associated to infectivity is crucial.
In this project, using two scrapie isolates with radically different abnormal PrP characteristics, we propose to fractionate PrP species present in infectious homogenates according to their density as to separate monomers from oligomers and multimers. We will then (i) measure infectivity of each fraction and (ii) characterize properties of PrP species associated to those fractions. Finally using precipitation approaches we will try to determine if immobilisation on solid phase is able to alter infectious power (making them more or less infectious for animal) of separated monomers, oligomers and multimers.
This project should bring valuable elements for
(i) developing more reliable TSE diagnosis tests that would correlate to infectivity presence.
(ii) progressing in our understanding of molecular pathogenesis of prion replication.
Project Documents
• FRP - Final Report : Infectivity associated to PrP aggregate fractions   (7840k)
Time-Scale and Cost
From: 2007

To: 2010

Cost: £77,906
Contractor / Funded Organisations
UMR INRA ENVT 1225, Service de Pharmacologie et d, UR 1282 INRA IASP
Keywords
Aggregates              
Animal Health              
Diagnosis              
Plants and Animals              
Scrapie              
TSE              
TSEs