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A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases

  • P2-318
  • 藤田 慶大 / Kyota Fujita:1 中村 蓉子 / Yoko Nakamura:1 岡 努 / Tsutomu Oka:1 伊藤 日加瑠 / Hikaru Ito:1 田村 拓也 / Takuya Tamura:1 田川 一彦 / Kazuhiko Tagawa:1 笹邊 俊和 / Toshikazu Sasabe:1 勝田 明寿香 / Asuka Katsuta:2 本木 和美 / Kazumi Motoki:1 塩飽 裕紀 / Hiroki Shiwaku:1 曽根 雅紀 / Masaki Sone:2 吉田 千里 / Chisato Yoshida:1 岡澤 均 / Hitoshi Okazawa:1 
  • 1:東京医科歯科大学 / Tokyo Medical and Dental University 2:東邦大学理学部生物分子科学科 / Dept Biomol Sci, faculty of Sci, Toho Univ, Japan 

It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. Here we show that transitional endoplasmic reticulum ATPase (TERA)/valosin-containing protein (VCP)/p97 directly binds to multiple polyglutamine disease proteins (huntingtin, ataxin-1, ataxin-7 and androgen receptor) via polyglutamine sequence. Although normal and mutant polyglutamine proteins interact with TERA/VCP/p97, only mutant proteins affect dynamism of TERA/VCP/p97. Among multiple functions of TERA/VCP/p97, we reveal that functional defect of TERA/VCP/p97 in DNA double-stranded break repair is critical for the pathology of neurons in which TERA/VCP/p97 is located dominantly in the nucleus in vivo. Mutant polyglutamine proteins impair accumulation of TERA/VCP/p97 and interaction of related double-stranded break repair proteins, finally causing the increase of unrepaired double-stranded break. Consistently, the recovery of lifespan in polyglutamine disease fly models by TERA/VCP/p97 corresponds well to the improvement of double-stranded break in neurons. Taken together, our results provide a novel common pathomechanism in multiple polyglutamine diseases that is mediated by DNA repair function of TERA/VCP/p97.

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