Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration
Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration
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DOI：
10.1093/brain/awv008
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发表时间：
2015-04-01
期刊：
影响因子：
14.5
通讯作者：
Chrast, Roman
中科院分区：
文献类型：
--
作者：
Bernard-Marissal, Nathalie;Medard, Jean-Jacques;Chrast, Roman
SIGMAR 1（编码Sigma 1受体）的突变导致肌萎缩侧索硬化症的家族性形式，但潜在的分子机制尚不清楚。Bernard-Marissal等揭示，σ 1受体功能的破坏扰乱内质网-线粒体相互作用和功能，导致运动神经元特异性变性，σ 1受体（SIGMAR 1）突变先前已在肌萎缩侧索硬化症患者中鉴定，并且小鼠中σ 1的破坏导致运动缺陷。然而，到目前为止，SIGMAR 1功能紊乱的人和小鼠中运动表型的细胞机制还没有被描述。在这里，我们使用了体内和体外的方法相结合，以研究SIGMAR 1在运动神经元生物学中的作用。Sigmar 1（-/-）小鼠的特征显示，受影响的动物表现出与肌肉无力、轴突变性和运动神经元损失相关的运动缺陷。使用原代运动神经元培养物，我们观察到SIGMAR 1的药理学或遗传失活导致运动神经元轴突变性，随后细胞死亡。运动神经元中SIGMAR 1功能的破坏扰乱了内质网-线粒体接触，影响了细胞内钙信号传导，并伴随着内质网应激的激活和线粒体动力学和转运的缺陷。在培养的感觉神经元中没有观察到这些缺陷，突出了运动神经元对SIGMAR 1功能的敏感性加剧。有趣的是，线粒体分裂的抑制足以诱导线粒体轴突运输缺陷以及轴突变性，类似于SIGMAR 1失活或丢失后观察到的变化。细胞内钙清除和内质网应激抑制能够恢复线粒体功能，从而防止运动神经元变性。这些结果揭示了由SIGMAR 1功能丧失介导的运动神经元变性的细胞机制，并为运动神经元疾病提供了治疗相关的见解。
Mutations in SIGMAR1, which encodes the Sigma 1 receptor, cause a familial form of amyotrophic lateral sclerosis, but the underlying molecular mechanisms are unclear. Bernard-Marissal et al. reveal that disruption of Sigma 1 receptor function disturbs endoplasmic reticulum-mitochondria interactions and functions, resulting in degeneration specifically of motor neurons.Mutations in Sigma 1 receptor (SIGMAR1) have been previously identified in patients with amyotrophic lateral sclerosis and disruption of Sigmar1 in mouse leads to locomotor deficits. However, cellular mechanisms underlying motor phenotypes in human and mouse with disturbed SIGMAR1 function have not been described so far. Here we used a combination of in vivo and in vitro approaches to investigate the role of SIGMAR1 in motor neuron biology. Characterization of Sigmar1(-/-) mice revealed that affected animals display locomotor deficits associated with muscle weakness, axonal degeneration and motor neuron loss. Using primary motor neuron cultures, we observed that pharmacological or genetic inactivation of SIGMAR1 led to motor neuron axonal degeneration followed by cell death. Disruption of SIGMAR1 function in motor neurons disturbed endoplasmic reticulum-mitochondria contacts, affected intracellular calcium signalling and was accompanied by activation of endoplasmic reticulum stress and defects in mitochondrial dynamics and transport. These defects were not observed in cultured sensory neurons, highlighting the exacerbated sensitivity of motor neurons to SIGMAR1 function. Interestingly, the inhibition of mitochondrial fission was sufficient to induce mitochondria axonal transport defects as well as axonal degeneration similar to the changes observed after SIGMAR1 inactivation or loss. Intracellular calcium scavenging and endoplasmic reticulum stress inhibition were able to restore mitochondrial function and consequently prevent motor neuron degeneration. These results uncover the cellular mechanisms underlying motor neuron degeneration mediated by loss of SIGMAR1 function and provide therapeutically relevant insight into motor neuronal diseases.