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

It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. We here show that TERA/VCP/p97 directly binds to multiple polyQ disease proteins (huntingtin, ataxin-1, ataxin-7, and androgen receptor) via polyQ sequence. Although normal and mutant polyQ proteins int...

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Published in:Nature communications 2013-01, Vol.4, p.1816-1816
Main Authors: Fujita, Kyota, Nakamura, Yoko, Oka, Tsutomu, Ito, Hikaru, Tamura, Takuya, Tagawa, Kazuhiko, Sasabe, Toshikazu, Katsuta, Asuka, Motoki, Kazumi, Shiwaku, Hiroki, Sone, Masaki, Yoshida, Chisato, Katsuno, Masahisa, Eishi, Yoshinobu, Murata, Miho, Taylor, J. Paul, Wanker, Erich E., Kono, Kazuteru, Tashiro, Satoshi, Sobue, Gen, La Spada, Albert R., Okazawa, Hitoshi
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Language:English
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Summary:It is hypothesized that a common underlying mechanism links multiple neurodegenerative disorders. We here show that TERA/VCP/p97 directly binds to multiple polyQ disease proteins (huntingtin, ataxin-1, ataxin-7, and androgen receptor) via polyQ sequence. Although normal and mutant polyQ 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 strand break (DSB) repair is critical for the pathology of neurons in which TERA/VCP/p97 is located dominantly in the nucleus in vivo . Mutant polyQ proteins impair accumulation of TERA/VCP/p97 and interaction of related DSB repair proteins, finally causing the increase of unrepaired DSB. Consistently, the recovery of lifespan in polyQ disease fly models by TERA/VCP/p97 corresponds well to the improvement of DSB in neurons. Taken together, our results provide a novel common pathomechanism in multiple polyQ diseases that is mediated by DNA repair function of TERA/VCP/p97.
ISSN:2041-1723
DOI:10.1038/ncomms2828