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TERA/VCP/p97 的功能缺陷导致多种多聚谷氨酰胺疾病的 DNA 修复受损。

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

机构信息

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.

出版信息

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

DOI:10.1038/ncomms2828
PMID:23652004
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4543262/
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.

摘要

据推测，多种神经退行性疾病存在共同的潜在发病机制。在这里，我们发现内质网过渡态 ATP 酶（TERA）/包含缬氨酸的蛋白（VCP）/ p97 可通过多聚谷氨酰胺序列直接与多种多聚谷氨酰胺疾病蛋白（亨廷顿蛋白、ataxin-1、ataxin-7 和雄激素受体）结合。虽然正常和突变的多聚谷氨酰胺蛋白均可与 TERA/VCP/p97 相互作用，但只有突变蛋白会影响 TERA/VCP/p97 的动力学。在 TERA/VCP/p97 的多种功能中，我们揭示了其在 DNA 双链断裂修复中的功能缺陷对于 TERA/VCP/p97 主要位于体内细胞核中的神经元的病理学至关重要。突变的多聚谷氨酰胺蛋白会损害 TERA/VCP/p97 的积累及其相关双链断裂修复蛋白的相互作用，最终导致未修复的双链断裂增加。一致地，多聚谷氨酰胺疾病果蝇模型中 TERA/VCP/p97 的寿命恢复与神经元中双链断裂的改善情况较好地吻合。综上，我们的研究结果为多种多聚谷氨酰胺疾病提供了一个新的共同发病机制，该机制由 TERA/VCP/p97 的 DNA 修复功能介导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4bf/4543262/3db9504244a3/nihms-714757-f0008.jpg
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