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Génération d’un nouveau prion spontané et analyse biologique et structurale de fibres amyloïdes lui correspondant

Abstract : Prions result from conformational change of the PrP protein and are responsible for fatal and transmissible neurodegenerative diseases in humans and animals. The modified form of PrP is insoluble, resistant to proteases and forms betaK sheetKrich aggregates. Prions convert the normal cellular PrP into a prion component by simple contact and thus expend in the brain. We showed that a deletion shortening the H2 helix of ovine PrP reduces protein stability and induced its spontaneous conversion into a new type of prion in a cell culture model. This new príon produced transconformation of the mutant PrP and its C1 fragment. C1 is a shortened form of PrP, NKterminally truncated by metalloproteases, but present with fullKlength PrP at the cell surface. The C1 fragment is not converted by classical prion strains and was considered too short to form a prion. Instead, we showed that the C1 of the mutant PrP can adopt a selfKreplicating, proteaseKresistant and infectious prion structure. Furthermore, amyloid fibrils produced in&vitro with a recombinant PrP harboring the deletion behaved as synthetic prions, inducing the conversion of the homologous cellular PrP and its C1 fragment into prion. Solid state NMR analysis of fibrils showed a conformational change to a betaKsheet enriched form in the CKterminal region.
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Submitted on : Wednesday, January 26, 2022 - 1:14:09 PM
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Djabir Larkem. Génération d’un nouveau prion spontané et analyse biologique et structurale de fibres amyloïdes lui correspondant. Biochimie, Biologie Moléculaire. Université Paris-Saclay, 2021. Français. ⟨NNT : 2021UPASB030⟩. ⟨tel-03544006⟩



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