ID 112312
Author
Uchida, Tsukasa Kyoto University
Tamaki, Yoshitaka Kyoto University
Ayaki, Takashi Kyoto University
Shodai, Akemi Kyoto University
Kaji, Seiji Kyoto University
Morimura, Toshifumi Shiga University of Medical Science
Banno, Yoshinori Shiga University of Medical Science
Maki, Takakuni Kyoto University
Yamashita, Hirofumi Kyoto University
Ito, Hidefumi Wakayama Medical University
Takahashi, Ryosuke Kyoto University
Urushitani, Makoto Kyoto University
Content Type
Journal Article
Description
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.
Journal Title
Scientific Reports
ISSN
20452322
Publisher
Springer Nature
Volume
6
Start Page
19118
Published Date
2016-01-11
Remark
Supplementary Information : srep_6_19118_s1.pdf
Rights
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/
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DOI (Published Version)
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language
eng
TextVersion
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departments
Medical Sciences