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Nat Commun. 2013;4:1816. doi: 10.1038/ncomms2828.

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

Author information

1
Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
2
Department of Biomolecular Science, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
3
Department of Neurology, Graduate School of Medicine, Nagoya University, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
4
Department of Human Pathology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
5
Department of Neurology, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan.
6
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
7
Department of Neurogenetics, Max-Delbrück Center for Molecular Medicine, 13125 Berlin-Buch, Germany.
8
Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
9
Departments of Pediatrics, Cellular & Molecular Medicine, and Neurosciences, Division of Biological Sciences, and the Institute for Genomic Medicine, University of California, San Diego; La Jolla, CA 92093, USA.
10
CREST, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi 332-0012, Japan.
#
Contributed equally

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.

PMID:
23652004
PMCID:
PMC4543262
DOI:
10.1038/ncomms2828
[Indexed for MEDLINE]
Free PMC Article

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