| Item type |
文献 / Documents(1) |
| 公開日 |
2017-08-10 |
| アクセス権 |
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|
アクセス権 |
open access |
| 資源タイプ |
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資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
|
資源タイプ |
journal article |
| 出版社版DOI |
|
|
|
識別子タイプ |
DOI |
|
|
関連識別子 |
https://doi.org/10.1371/journal.ppat.1006470 |
| 出版タイプ |
|
|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
|
|
タイトル |
Prions amplify through degradation of the VPS10P sorting receptor sortilin |
|
言語 |
en |
| 著者 |
内山, 圭司
トミタ, ミツル
矢野, 雅司
千田, 淳司
原, 英之
Das, Nandita Rani
Nykjaer, Anders
坂口, 末廣
|
| 抄録 |
|
|
内容記述タイプ |
Abstract |
|
内容記述 |
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. |
|
言語 |
en |
| 書誌情報 |
en : PLOS Pathogens
巻 13,
号 6,
p. e1006470,
発行日 2017-06-30
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| 収録物ID |
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収録物識別子タイプ |
ISSN |
|
収録物識別子 |
15537366 |
| 収録物ID |
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収録物識別子タイプ |
ISSN |
|
収録物識別子 |
15537374 |
| 収録物ID |
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収録物識別子タイプ |
NCID |
|
収録物識別子 |
AA12072310 |
| 権利情報 |
|
|
言語 |
en |
|
権利情報 |
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. |
| EID |
|
|
識別子 |
328699 |
|
識別子タイプ |
URI |
| 言語 |
|
|
言語 |
eng |
plospathog_13_6_e1006470.pdf (9.28 MB)
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