Fujita, K., Nakamura, Y., Oka, T., Ito, H., Tamura, T., Tagawa, K., Sasabe, T., Katsuta, A., Motoki, K., Shiwaku, H., Sone, M., Yoshida, C., Katsuno, M., Eishi, Y., Murata, M., Taylor, J.P., Wanker, E.E., Kono, K., Tashiro, S., Sobue, G., La Spada, A.R., Okazawa, H. (2013). A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases.  Nat. Commun. 4(): 1816.

FBrf0223593

Research paper

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.

PMC4543262 (PMC) (EuropePMC)