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

• Published in: Nature communications 2013-05, Vol.4 (1), p.1816-1816, Article 1816
• Main Authors: Fujita, Kyota, Nakamura, Yoko, Oka, Tsutomu, Ito, Hikaru, Tamura, Takuya, Tagawa, Kazuhiko, Sasabe, Toshikazu, Katsuta, Asuka, Motoki, Kazumi, Shiwaku, Hiroki, Sone, Masaki, Yoshida, Chisato, Katsuno, Masahisa, Eishi, Yoshinobu, Murata, Miho, Paul Taylor, J., Wanker, Erich E., Kono, Kazuteru, Tashiro, Satoshi, Sobue, Gen, La Spada, Albert R., Okazawa, Hitoshi
• Format: Article
• Language: English
• Subjects: 631/337/1427; 631/378/1689; 631/80/304; Adenosine Triphosphatases - deficiency; Adenosine Triphosphatases - metabolism; Animals; Animals, Genetically Modified; Ataxia; Ataxin-1; Ataxins; Cell Cycle Proteins - deficiency; Cell Cycle Proteins - metabolism; Cerebral Cortex - pathology; Disease; DNA Breaks, Double-Stranded; DNA Repair; Drosophila melanogaster - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Green Fluorescent Proteins - metabolism; HEK293 Cells; HeLa Cells; Histones - metabolism; Humanities and Social Sciences; Humans; Immunoprecipitation; Inclusion Bodies - metabolism; Longevity; Medicine; Mice; Motor Neurons - metabolism; Motor Neurons - pathology; multidisciplinary; Mutant Proteins - metabolism; Nerve Tissue Proteins - metabolism; Neurodegeneration; Neurology; Neurons; Neurosciences; Nuclear Proteins - metabolism; Pathology; Peptides - metabolism; Phenotype; Protein Binding; Protein Transport; Proteins; Science; Science (multidisciplinary); Valosin Containing Protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2828

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. Mutations in polyglutamine proteins are implicated in neurodegenerative disorders. Okazawa and colleagues now demonstrate that mutant polyQ proteins interact directly with the ATPase TERA, resulting in reduced DNA double-strand break repair, which is a feature of neurodegenerative diseases.