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ID 110433
著者
内山, 圭司 Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University KAKEN研究者をさがす
トミタ, ミツル Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University|Student Laboratory, Faculty of Medicine, Tokushima University
矢野, 雅司 Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
千田, 淳司 Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
原, 英之 Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
Das, Nandita Rani Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University
Nykjaer, Anders Department of Biomedicine, Aarhus University
坂口, 末廣 Division of Molecular Neurobiology, Institute for Enzyme Research (KOSOKEN), Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
資料タイプ
学術雑誌論文
抄録
Prion diseases are a group of fatal neurodegenerative disorders caused by prions, which consist mainly of the abnormally folded isoform of prion protein, PrPSc. A pivotal pathogenic event in prion disease is progressive accumulation of prions, or PrPSc, in brains through constitutive conformational conversion of the cellular prion protein, PrPC, into PrPSc. However, the cellular mechanism by which PrPSc is progressively accumulated in prion-infected neurons remains unknown. Here, we show that PrPSc is progressively accumulated in prion-infected cells through degradation of the VPS10P sorting receptor sortilin. We first show that sortilin interacts with PrPC and PrPSc and sorts them to lysosomes for degradation. Consistently, sortilin-knockdown increased PrPSc accumulation in prion-infected cells. In contrast, overexpression of sortilin reduced PrPSc accumulation in prion-infected cells. These results indicate that sortilin negatively regulates PrPSc accumulation in prion-infected cells. The negative role of sortilin in PrPSc accumulation was further confirmed in sortilin-knockout mice infected with prions. The infected mice had accelerated prion disease with early accumulation of PrPSc in their brains. Interestingly, sortilin was reduced in prion-infected cells and mouse brains. Treatment of prion-infected cells with lysosomal inhibitors, but not proteasomal inhibitors, increased the levels of sortilin. Moreover, sortilin was reduced following PrPSc becoming detectable in cells after infection with prions. These results indicate that PrPSc accumulation stimulates sortilin degradation in lysosomes. Taken together, these results show that PrPSc accumulation of itself could impair the sortilin-mediated sorting of PrPC and PrPSc to lysosomes for degradation by stimulating lysosomal degradation of sortilin, eventually leading to progressive accumulation of PrPSc in prion-infected cells.
掲載誌名
PLOS Pathogens
ISSN
15537366
15537374
cat書誌ID
AA12072310
13
6
開始ページ
e1006470
並び順
1006470
発行日
2017-06-30
備考
Copyright: © 2017 Uchiyama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
EDB ID
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
出版社版
部局
先端酵素学研究所
技術支援部