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
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資料タイプ |
学術雑誌論文
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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.
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掲載誌名 |
PLOS Pathogens
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ISSN | 15537366
15537374
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cat書誌ID | AA12072310
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巻 | 13
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号 | 6
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開始ページ | e1006470
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並び順 | 1006470
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発行日 | 2017-06-30
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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.
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EDB ID | |
出版社版URL | |
フルテキストファイル | |
言語 |
eng
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著者版フラグ |
出版社版
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部局 |
先端酵素学研究所
技術支援部
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