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- W2085600877 abstract "Misfolding of PrPC (cellular prion protein) to β-strand-rich conformations constitutes a key event in prion disease pathogenesis. PrPC can undergo either of two constitutive endoproteolytic events known as α- and β-cleavage, yielding C-terminal fragments known as C1 and C2 respectively. It is unclear whether C-terminal fragments generated through α- and β-cleavage, especially C2, influence pathogenesis directly. Consequently, we compared the biophysical properties and neurotoxicity of recombinant human PrP fragments recapitulating α- and β-cleavage, namely huPrP-(112–231) (equating to C1) and huPrP-(90–231) (equating to C2). Under conditions we employed, huPrP-(112–231) could not be induced to fold into a β-stranded isoform and neurotoxicity was not a feature for monomeric or multimeric assemblies. In contrast, huPrP-(90–231) easily adopted a β-strand conformation, demonstrated considerable thermostability and was toxic to neurons. Synthetic PrP peptides modelled on α- and β-cleavage of the unique Y145STOP (Tyr145→stop) mutant prion protein corroborated the differential toxicity observed for recombinant huPrP-(112–231) and huPrP-(90–231) and suggested that the persistence of soluble oligomeric β-strand-rich conformers was required for significant neurotoxicity. Our results additionally indicate that α- and β-cleavage of PrPC generate biophysically and biologically non-equivalent C-terminal fragments and that C1 generated through α-cleavage appears to be pathogenesis-averse." @default.
- W2085600877 created "2016-06-24" @default.
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- W2085600877 date "2014-03-14" @default.
- W2085600877 modified "2023-10-14" @default.
- W2085600877 title "C-terminal peptides modelling constitutive PrPC processing demonstrate ameliorated toxicity predisposition consequent to α-cleavage" @default.
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- W2085600877 doi "https://doi.org/10.1042/bj20131378" @default.
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