Sequence-dependent Prion Protein Misfolding and Neurotoxicity |
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| Authors: | Pedro Fernandez-Funez Yan Zhang Sergio Casas-Tinto Xiangzhu Xiao Wen-Quan Zou Diego E. Rincon-Limas |
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| Affiliation: | From the Departments of ‡Neurology and ;§Neurosciences, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610.;the ¶Department of Molecular Oncology, Centro Nacional de Investigaciones Oncologicas, E-28029 Madrid, Spain, and ;the ‖Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106 |
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| Abstract: | 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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| Keywords: | Drosophila Neurodegeneration Neurological Diseases Prions Protein Conformation Disease Model |
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