Aggregation of FET Proteins as a Pathological Change in Amyotrophic Lateral Sclerosis.
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.
Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku, Yokohama, 223-8522, Japan. furukawa@chem.keio.ac.jp.
Yoshiaki
Y
Furukawa
Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, Keio University, 3-14-1 Hiyoshi, Kohoku, Yokohama, 223-8522, Japan.
Eiichi
E
Tokuda
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D066329:Protein Aggregates / Q000235:genetics; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics* / Q000378:metabolism
D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; C000599550:FUS protein, human; D066329:Protein Aggregates; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; C102041:TAF15 protein, human; D035381:TATA-Binding Protein Associated Factors
Amyotrophic lateral sclerosis; FET family proteins; FUS; Neurodegenerative diseases; Protein aggregation