| Literature DB >> 23652004 |
Kyota Fujita1, Yoko Nakamura1, Tsutomu Oka1, Hikaru Ito1, Takuya Tamura1, Kazuhiko Tagawa1, Toshikazu Sasabe1, Asuka Katsuta1,2, Kazumi Motoki1, Hiroki Shiwaku1, Masaki Sone1,2, Chisato Yoshida1, Masahisa Katsuno3, Yoshinobu Eishi4, Miho Murata5, J Paul Taylor6, Erich E Wanker7, Kazuteru Kono8, Satoshi Tashiro8, Gen Sobue3, Albert R La Spada9, Hitoshi Okazawa1,10.
Abstract
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.Entities:
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Year: 2013 PMID： 23652004 PMCID： PMC4543262 DOI： 10.1038/ncomms2828
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919