title: A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases.
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.
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Kyota
authors: K
authors: Fujita
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Yoko
authors: Y
authors: Nakamura
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Tsutomu
authors: T
authors: Oka
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Hikaru
authors: H
authors: Ito
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Takuya
authors: T
authors: Tamura
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Kazuhiko
authors: K
authors: Tagawa
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Toshikazu
authors: T
authors: Sasabe
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.|Department of Biomolecular Science, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors: Asuka
authors: A
authors: Katsuta
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Kazumi
authors: K
authors: Motoki
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Hiroki
authors: H
authors: Shiwaku
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.|Department of Biomolecular Science, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan.
authors: Masaki
authors: M
authors: Sone
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Chisato
authors: C
authors: Yoshida
authors: Department of Neurology, Graduate School of Medicine, Nagoya University, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors: Masahisa
authors: M
authors: Katsuno
authors: Department of Human Pathology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors: Yoshinobu
authors: Y
authors: Eishi
authors: Department of Neurology, National Center of Neurology and Psychiatry, 4-1-1, Ogawahigashimachi, Kodaira, Tokyo 187-8551, Japan.
authors: Miho
authors: M
authors: Murata
authors: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors: J Paul
authors: JP
authors: Taylor
authors: Department of Neurogenetics, Max-Delbrück Center for Molecular Medicine, 13125 Berlin-Buch, Germany.
authors: Erich E
authors: EE
authors: Wanker
authors: Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors: Kazuteru
authors: K
authors: Kono
authors: Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors: Satoshi
authors: S
authors: Tashiro
authors: Department of Neurology, Graduate School of Medicine, Nagoya University, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors: Gen
authors: G
authors: Sobue
authors: 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.
authors: Albert R
authors: AR
authors: La Spada
authors: Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.|CREST, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi 332-0012, Japan.
authors: Hitoshi
authors: H
authors: Okazawa
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D000067696:Ataxin-1; D000067528:Ataxins; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004331:Drosophila melanogaster / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D002479:Inclusion Bodies / Q000378:metabolism; D008136:Longevity; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D000074405:Valosin Containing Protein
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D018797:Cell Cycle Proteins; D006657:Histones; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C097188:polyglutamine; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse
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