Aggregation of FET Proteins as a Pathological Change in Amyotrophic Lateral Sclerosis

Abstract

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.

The roles of intrinsic disorder-based liquid-liquid phase transitions in the “Dr. Jekyll–Mr. Hyde” behavior of proteins involved in amyotrophic lateral sclerosis and frontotemporal lobar degeneration

“…396 The FUS gene is positioned within chromosome 16 (its cytogenic location is 16p11. 397,398 Human FUS (UniProt ID: P35637) contains several distinct functional domains including a RNA-recognition motif and a highly-conserved C-terminal NLS. 395 This C-terminal domain is a hot-spot for the identified ALS-related mutations.…”

Potential proteomic alteration in the brain of Tg(SOD1*G93A)1Gur mice: A new pathogenesis insight of amyotrophic lateral sclerosis

“…However, to date, the precise cellular components and related mechanisms damaged by abnormally expressed proteins have remained unclear (Almad et al, 2016;Clark et al, 2016;Furukawa & Tokuda, 2017;Guerrero et al, 2016;Kamelgarn et al, 2016;Martin & Chang, 2012;Prpar Mihevc et al, 2016;Z.-D. Zhou et al, 2017). The GO enrichment analysis indicated that the abnormally expressed proteins were extensively distributed in various cellular components, the most relevant of which were the muscle-related components, including the contractile fiber, the striated muscle thin filament and myofibril, and the axon-related components, such as the paranode and juxtaparanode regions of the axon (Table 1) (Almad et al, 2016;Clark et al, 2016;Furukawa & Tokuda, 2017;Guerrero et al, 2016;Kamelgarn et al, 2016;Martin & Chang, 2012;Prpar Mihevc et al, 2016;Z.-D. Zhou et al, 2017). These findings suggested that lesions of muscle-and axon-related proteins were a key pathological basis of ALS.…”

Serum asymmetric dimethylarginine level correlates with the progression and prognosis of amyotrophic lateral sclerosis

“…Interestingly, recent reports have shown that RNA-binding proteins that are targets of arginine dimethylation demonstrate abnormal aggregation or mislocalization in the motor neurons of sporadic ALS patients [4][5][6][7], indicating the involvement of abnormal arginine dimethylation in the pathogenesis of ALS.…”

“…It is hence hypothesized that increased CSF ADMA levels might reflect the hypermethylation of RNA‐binding proteins in the spinal motor neurons and surrounding glial cells of ALS disease patients. Interestingly, recent reports have shown that RNA‐binding proteins that are targets of arginine dimethylation demonstrate abnormal aggregation or mislocalization in the motor neurons of sporadic ALS patients [ 4 , 5 , 6 , 7 ], indicating the involvement of abnormal arginine dimethylation in the pathogenesis of ALS.…”