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.
Bibliographical noteFunding Information:
This work was supported by a Grant-in-aid for Scientific Research on Innovative Areas (Foundation of Synapse and Neurocircuit Pathology) and Strategic Research Program for Brain Sciences (SRPBS) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; CREST from Japan Science Technology Agency; a Grant-in-aid from the Research Committee for Ataxic Disease from the Ministry of Health, Labour and Welfare to HO; and R01s NS41648 and AG33082 to ARL. We thank Prof. Huda Y. Zoghbi (Baylor College of Medicine) and Dr Kei Watase (TMDU) for the ATXN1-KI mice, Professor Marcy MacDonald (Harvard Medical School) for the Htt-KI mice, Professor Tom A. Rapoport (Harvard Medical School) for the Derlin-1 antibody and technical advice, Professor Diane Merry (Thomas Jefferson University) for the AR plasmids, and Professor Len Neckers (National Institute of Health) for the ErbB2 plasmid, Professor Randall Pittman (University of Pennsylvania) for the pCI-neo-HA-CD3d plasmid, and Prof. Tamotsu Yoshitomi (National Institute for Basic Biology) and Prof. Noboru Mizushima (Tokyo Medical and Dental University) for the pEGFP-LC3. We thank Dr Kei Watase (Tokyo Medical and Dental University) for technical support and critical discussion. We also thank Ms Chie IInuma, Ms Chiharu Mizoi, Ms Aiko Unno, Ms Chiharu Nagashima and Ms Tayoko Tajima for technical support.