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タイトル: CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS.
著者: Uchida, Tsukasa
Tamaki, Yoshitaka
Ayaki, Takashi  kyouindb  KAKEN_id
Shodai, Akemi
Kaji, Seiji
Morimura, Toshifumi
Banno, Yoshinori
Nishitsuji, Kazuchika
Sakashita, Naomi
Maki, Takakuni  kyouindb  KAKEN_id
Yamashita, Hirofumi
Ito, Hidefumi
Takahashi, Ryosuke  kyouindb  KAKEN_id
Urushitani, Makoto
著者名の別形: 内田, 司
伊東, 秀文
漆谷, 真
発行日: 11-Jan-2016
出版者: Nature Publishing Group
誌名: Scientific reports
巻: 6
論文番号: 19118
抄録: The molecular machinery responsible for cytosolic accumulation of misfolded TDP-43 in amyotrophic lateral sclerosis (ALS) remains elusive. Here we identified a cullin-2 (CUL2) RING complex as a novel ubiquitin ligase for fragmented forms of TDP-43. The von Hippel Lindau protein (VHL), a substrate binding component of the complex, preferentially recognized misfolded TDP-43 at Glu246 in RNA-recognition motif 2. Recombinant full-length TDP-43 was structurally fragile and readily cleaved, suggesting that misfolded TDP-43 is cleared by VHL/CUL2 in a step-wise manner via fragmentation. Surprisingly, excess VHL stabilized and led to inclusion formation of TDP-43, as well as mutant SOD1, at the juxtanuclear protein quality control center. Moreover, TDP-43 knockdown elevated VHL expression in cultured cells, implying an aberrant interaction between VHL and mislocalized TDP-43 in ALS. Finally, cytoplasmic inclusions especially in oligodendrocytes in ALS spinal cords were immunoreactive to both phosphorylated TDP-43 and VHL. Thus, our results suggest that an imbalance in VHL and CUL2 may underlie oligodendrocyte dysfunction in ALS, and highlight CUL2 E3 ligase emerges as a novel therapeutic potential for ALS.
記述: 神経難病・筋萎縮性側索硬化症の病原蛋白質を分解する新たな仕組みを発見 -ALSの新たな病態の発見と分子標的治療の可能性を開く-. 京都大学プレスリリース. 2016-01-12.
著作権等: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
URI: http://hdl.handle.net/2433/203055
DOI(出版社版): 10.1038/srep19118
PubMed ID: 26751167
関連リンク: http://www.kyoto-u.ac.jp/ja/research/research_results/2015/160111_1.html
出現コレクション:学術雑誌掲載論文等

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