Division of Life Sciences, Korea University, Seoul 02841, Korea.
Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
Int J Mol Sci. 2020 Oct 13;21(20):7525. doi: 10.3390/ijms21207525.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive demise of motor neurons. One of the causes of familial ALS is the mutation of the gene encoding superoxide dismutase 1 (SOD1), which leads to abnormal protein aggregates. How SOD1 aggregation drives ALS is still poorly understood. Recently, ALS pathogenesis has been functionally implicated in mitophagy, specifically the clearance of damaged mitochondria. Here, to understand this mechanism, we investigated the relationship between the mitophagy receptor optineurin and SOD1 aggregates. We found that mutant SOD1 (mSOD1) proteins associate with and then sequester optineurin, which is required to form the mitophagosomes, to aggregates in N2a cells. Optineurin recruitment into mSOD1 aggregates resulted in a reduced mitophagy flux. Furthermore, we observed that an exogenous augmentation of optineurin alleviated the cellular cytotoxicity induced by mSOD1. Taken together, these studies demonstrate that ALS-linked mutations in SOD1 interfere with the mitophagy process through optineurin sequestration, suggesting that the accumulation of damaged mitochondria may play a crucial role in the pathophysiological mechanisms contributing to ALS.
肌萎缩侧索硬化症（ALS）是一种神经退行性疾病，其特征是运动神经元的进行性死亡。家族性 ALS 的一个原因是编码超氧化物歧化酶 1（SOD1）的基因突变，导致异常的蛋白质聚集。SOD1 聚集如何导致 ALS 仍然知之甚少。最近，ALS 的发病机制在功能上与自噬有关，特别是受损线粒体的清除。在这里，为了理解这种机制，我们研究了自噬受体视神经萎缩症蛋白（optineurin）与 SOD1 聚集体之间的关系。我们发现突变型 SOD1（mSOD1）蛋白与 optineurin 结合，然后将其隔离到形成自噬体所需的位置，形成 N2a 细胞中的聚集体。optineurin 被招募到 mSOD1 聚集体中，导致自噬通量减少。此外，我们观察到外源性增加 optineurin 可以减轻 mSOD1 诱导的细胞毒性。总之，这些研究表明，ALS 相关的 SOD1 突变通过 optineurin 的隔离干扰了自噬过程，这表明受损线粒体的积累可能在导致 ALS 的病理生理机制中起关键作用。
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