Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS

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• 作者：Seiji Watanabe ; Hristelina Ilieva ; Hiromi Tamada ; Hanae Nomura ; Okiru Komine ; Fumito Endo ; Shijie Jin ; Pedro Mancias ; Hiroshi Kiyama and Koji Yamanaka
• 刊名：EMBO Molecular Medicine
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：8
• 期：12
• 页码：1421-1437
• 全文大小：5275K
• ISSN：1757-4684

文摘

A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria-associated membrane (MAM), which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM in ALS is not fully elucidated. Here, we identified a homozygous p.L95fs mutation of Sig1R as a novel cause of ALS16. ALS-linked Sig1R variants were unstable and incapable of binding to inositol 1,4,5-triphosphate receptor type 3 (IP₃R3). The onset of mutant Cu/Zn superoxide dismutase (SOD1)-mediated ALS disease in mice was accelerated when Sig1R was deficient. Moreover, either deficiency of Sig1R or accumulation of mutant SOD1 induced MAM disruption, resulting in mislocalization of IP₃R3 from the MAM, calpain activation, and mitochondrial dysfunction. Our findings indicate that a loss of Sig1R function is causative for ALS16, and collapse of the MAM is a common pathomechanism in both Sig1R- and SOD1-linked ALS. Furthermore, our discovery of the selective enrichment of IP₃R3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.