Sequence-dependent prion protein misfolding and neurotoxicity

Pedro Fernandez-Funez, Yan Zhang, Sergio Casas-Tinto, Xiangzhu Xiao, Wen Quan Zou, Diego E. Rincon-Limas

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


Prion diseases are neurodegenerative disorders caused by misfolding of the normal prion protein (PrP) into a pathogenic "scrapie" conformation. To better understand the cellular and molecular mechanisms that govern the conformational changes (conversion) of PrP, we compared the dynamics of PrP from mammals susceptible (hamster and mouse) and resistant (rabbit) to prion diseases in transgenic flies. We recently showed that hamster PrP induces spongiform degeneration and accumulates into highly aggregated, scrapie-like conformers in transgenic flies. We show now that rabbit PrP does not induce spongiform degeneration and does not convert into scrapie-like conformers. Surprisingly, mouse PrP induces weak neurodegeneration and accumulates small amounts of scrapie-like conformers. Thus, the expression of three highly conserved mammalian prion proteins in transgenic flies uncovered prominent differences in their conformational dynamics. How these properties are encoded in the amino acid sequence remains to be elucidated.

Original languageEnglish (US)
Pages (from-to)36897-36908
Number of pages12
JournalJournal of Biological Chemistry
Issue number47
StatePublished - Nov 19 2010


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