Mislocalization, aggregation formation and defect in proteolysis in ALS
Mislocalization, aggregation formation and defect in proteolysis in ALS
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DOI：
10.3934/molsci.2016.2.246
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发表时间：
2016-05
期刊：
影响因子：
82.9
通讯作者：
A. Tsubota;H. Ichijo;Kengo Homma
中科院分区：
文献类型：
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作者：
A. Tsubota;H. Ichijo;Kengo Homma
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种以运动神经元变性为特征的神经退行性疾病。在ALS中观察到的特征是蛋白质在受影响的运动神经元中的错误定位和聚集。导致ALS的Cu/Zn超氧化物歧化酶（SOD 1）或TAR DNA结合蛋白（TDP-43）的突变体已被报道异常定位。这些聚集体含有ALS致病基因的产物，包括SOD 1或TDP-43。值得注意的是，即使在散发性ALS病例中也已鉴定出TDP-43阳性聚集体，表明聚集体形成在ALS发病机制中的重要性。除了ALS致病基因产物之外的各种蛋白质也包括在这些聚集体中。据认为，遗传突变诱导的蛋白质构象变化引起异常的再分布和聚集体的形成，导致功能丧失或通过不期望的相互作用获得神经元毒性。此外，与蛋白水解系统相关的含valosin-containing蛋白（VCP）、ubiquilin 2（UBQLN 2）和optineurin（OPTN）也被鉴定为ALS的致病基因。这些事实表明，异常的蛋白质稳态介导的错误定位，聚集体的形成，或在蛋白水解系统的缺陷是ALS神经元毒性的根本原因。在这里，我们专注于ALS中观察到的蛋白质稳态受损，以讨论运动神经元毒性的可能性。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motoneuron degeneration. The features observed in ALS are the mislocalization and aggregation of proteins in the affected motoneurons. The mutants of Cu/Zn superoxide dismutase (SOD1) or TAR DNA binding protein (TDP-43) that cause ALS have been reported to localize aberrantly. These aggregations contain the products of ALS causative genes, including SOD1 or TDP-43. Notably, TDP-43-positive aggregations have been identified even in sporadic ALS cases, indicating the importance of aggregate formation in the pathogenesis of ALS. Various proteins other than ALS causative gene products are also included in these aggregates. It is thought that the genetic mutation-induced conformational changes of proteins cause the aberrant redistribution and formation of aggregates, resulting in a loss of function or a gain of neuronal toxicity through the undesired interactions. Additionally, valosin-containing protein (VCP) , u biquilin2 (UBQLN2) and optineurin (OPTN) , which are related to the proteolysis system, have also been identified as causative genes in ALS. These facts suggest that the aberrant protein homeostasis mediated by mislocalization, aggregate formation, or defects in the proteolysis system are the underlying causes of neuronal toxicity in ALS. Here, we focus on the impaired protein homeostasis observed in ALS to discuss the potential for motoneuron toxicity.