Sequence-dependent prion protein misfolding and neurotoxicity.
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.
Fernandez-Funez
Pedro
P
Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA. pedro.fernandez@neurology.ufl.edu
Zhang
Yan
Y
Casas-Tinto
Sergio
S
Xiao
Xiangzhu
X
Zou
Wen-Quan
WQ
Rincon-Limas
Diego E
DE
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002850:Chromatography, Gel; D017124:Conserved Sequence; D006224:Cricetinae; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D008124:Locomotion / Q000502:physiology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011328:Prions / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid
D011328:Prions; D012333:RNA, Messenger
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