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

• DOI: 10.1038/ncomms2828
• Publication Date: 2013-05-07T10:05:10Z
• Authors: Kyota Fujita; Yoko Nakamura; Tsutomu Oka; Hikaru Ito; Takuya Tamura; Kazuhiko Tagawa; Toshikazu Sasabe; Asuka Katsuta; Kazumi Motoki; Hiroki Shiwaku; Masaki Sone; Chisato Yoshida; Masahisa Katsuno; Yoshinobu Eishi; Miho Murata; J. Paul Taylor; Erich E. Wanker; Kazuteru Kono; Satoshi Tashiro; Gen Sobue; Albert R. La Spada; Hitoshi Okazawa
• Keywords: Adenosine Triphosphatases; Cerebral Cortex; Inclusion Bodies; 0301 basic medicine; DNA Repair; Green Fluorescent Proteins; Longevity; Cell Cycle Proteins; Endoplasmic Reticulum; Animals, Genetically Modified; Histones; Mice; 03 medical and health sciences; Drosophila melanogaster; HEK293 Cells; Ataxins; Animals; Humans; Immunoprecipitation; DNA Breaks, Double-Stranded; Ataxin-1; HeLa Cells

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.