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

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 and Hitoshi Okazawa ()
Additional contact information
Kyota Fujita: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Yoko Nakamura: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Tsutomu Oka: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Hikaru Ito: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Takuya Tamura: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Kazuhiko Tagawa: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Toshikazu Sasabe: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Asuka Katsuta: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Kazumi Motoki: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Hiroki Shiwaku: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Masaki Sone: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Chisato Yoshida: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Masahisa Katsuno: Graduate School of Medicine, Nagoya University, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Yoshinobu Eishi: Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
Miho Murata: National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashimachi, Kodaira 187-8551, Japan
J. Paul Taylor: St. Jude Children’s Research Hospital
Erich E. Wanker: Max-Delbrück Center for Molecular Medicine
Kazuteru Kono: Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan
Satoshi Tashiro: Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan
Gen Sobue: Graduate School of Medicine, Nagoya University, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Albert R. La Spada: Cellular and Molecular Medicine, and Neurosciences, and the Institute for Genomic Medicine, University of California, San Diego
Hitoshi Okazawa: Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2828

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