Journal Article CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS.

Uchida, Tsukasa  ,  Tamaki, Yoshitaka  ,  Ayaki, Takashi  ,  Shodai, Akemi  ,  Kaji, Seiji  ,  Morimura, Toshifumi  ,  Banno, Yoshinori  ,  Nishitsuji, Kazuchika  ,  Sakashita, Naomi  ,  Maki, Takakuni  ,  Yamashita, Hirofumi  ,  Ito, Hidefumi  ,  Takahashi, Ryosuke  ,  Urushitani, Makoto

62016-01-11 , Nature Publishing Group
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.
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.

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