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

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 925)

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.

Keywords

FUS FET family proteins Amyotrophic lateral sclerosis Protein aggregation Neurodegenerative diseases 

Notes

Acknowledgements

This work was supported by Grants-in-aid 25291028, 15H01566, 15K14480 (to Y.F.) and 15H06588 (to E.T.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Conflicts of Interest

The authors declare no conflict of interest.

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Laboratory for Mechanistic Chemistry of Biomolecules, Department of ChemistryKeio UniversityYokohamaJapan

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