Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS.
Mitochondria-associated membrane collapse is a common pathomechanism in SIGMAR1- and SOD1-linked ALS.
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DOI：
10.15252/emmm.201606403
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发表时间：
2016-12
影响因子：
11.1
通讯作者：
Yamanaka K
中科院分区：
文献类型：
--
作者：
Watanabe S;Ilieva H;Tamada H;Nomura H;Komine O;Endo F;Jin S;Mancias P;Kiyama H;Yamanaka K
sigma 1受体（Sig 1 R）基因的纯合突变是遗传性青少年肌萎缩侧索硬化症（ALS 16）的原因。Sig 1 R定位于线粒体相关膜（MAM），这是线粒体和内质网的界面。然而，MAM在ALS中的作用尚未完全阐明。在这里，我们确定了Sig 1 R的纯合p.L95fs突变作为ALS的新原因16。ALS连接的Sig 1 R变体不稳定，不能与肌醇1，4，5-三磷酸受体3型（IP 3R 3）结合。当Sig 1 R缺乏时，小鼠中突变型Cu/Zn超氧化物歧化酶（SOD 1）介导的ALS疾病的发病加速。此外，无论是Sig 1 R的缺陷或突变SOD 1的积累诱导MAM中断，导致IP 3R 3从MAM，钙蛋白酶激活和线粒体功能障碍的错误定位。我们的研究结果表明，Sig 1 R功能的丧失是ALS 16的病因，MAM的崩溃是Sig 1 R和SOD 1相关ALS的共同病理机制。此外，我们发现运动神经元中IP 3R 3的选择性富集表明MAM的完整性对于ALS中的选择性脆弱性至关重要。
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 (IP 3R3). 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 IP 3R3 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 IP 3R3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.