Aggregation of FET Proteins as a Pathological Change in Amyotrophic Lateral Sclerosis.
Aggregation of FET Proteins as a Pathological Change in Amyotrophic Lateral Sclerosis.
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DOI：
10.1007/5584_2016_32
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发表时间：
2017-01-01
影响因子：
--
通讯作者：
Tokuda, Eiichi
中科院分区：
文献类型：
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作者：
Furukawa, Yoshiaki;Tokuda, Eiichi
肌萎缩性侧索硬化症（ALS）是一种致命的运动神经元疾病，其特征是神经元中形成异常包涵体。虽然ALS的病理机制尚不清楚，但在包涵体中已经发现了许多蛋白质，rna结合蛋白的病理作用越来越受到重视。其中，FET蛋白（FUS, EWSR1, TAF15）最近被鉴定为ALS和其他神经退行性疾病病理包涵体中的rna结合蛋白；此外，编码FET蛋白的基因突变被发现与家族性ALS有关。FET蛋白通常定位于细胞核中，但在FET蛋白中引入致病性突变导致它们异常地重新分布到细胞质中，并在细胞质中形成聚集体。虽然需要进一步的研究来了解控制FET蛋白聚集倾向的细胞内因子，但它们被认为是通过错误折叠/聚集而失去生理功能并变得有毒的。在这里，我们将简要回顾我们对FET蛋白在体内和体外的生理功能和聚集行为的理解的最新进展。
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that is characterized by the formation of abnormal inclusions in neurons. While the pathomechanism of ALS remains obscure, a number of proteins have been identified in the inclusion bodies, and the pathological roles of RNA-binding proteins have been increasingly emphasized. Among those, the FET proteins (FUS, EWSR1, TAF15) were recently identified as RNA-binding proteins in pathological inclusions of ALS and other neurodegenerative diseases; moreover, mutations in the genes encoding the FET proteins were found to be associated with familial forms of ALS. FET proteins are normally localized in the nucleus, but the introduction of pathogenic mutations in FET proteins leads to their abnormal redistribution to the cytoplasm, where they form aggregates. While further investigation will be required to understand the intracellular factors controlling the aggregation propensities of FET proteins, they are thought to lose their physiological functions and become toxic through their misfolding/aggregation. Here, we will briefly review recent advances of our understanding of the physiological functions and aggregation behavior of FET proteins in vivo as well as in vitro.