TY - JOUR
T1 - Sequence-dependent prion protein misfolding and neurotoxicity
AU - Fernandez-Funez, Pedro
AU - Zhang, Yan
AU - Casas-Tinto, Sergio
AU - Xiao, Xiangzhu
AU - Zou, Wen Quan
AU - Rincon-Limas, Diego E.
PY - 2010/11/19
Y1 - 2010/11/19
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M110.174391
DO - 10.1074/jbc.M110.174391
M3 - Article
C2 - 20817727
AN - SCOPUS:78449260181
SN - 0021-9258
VL - 285
SP - 36897
EP - 36908
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 47
ER -