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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Mutations in related RNA-binding proteins TDP-43, FUS/TLS and TAF15 have been connected to ALS. These three proteins share several features, including the presence of a bioinformatics-predicted prion domain, aggregation–prone nature  in vitro  and  in vivo  and toxic effects when expressed in multiple model systems. Given these commonalities, we hypothesized that a related protein, EWSR1 (Ewing sarcoma breakpoint region 1), might also exhibit similar properties and therefore could contribute to disease. Here, we report an analysis of EWSR1 in multiple functional assays, including mutational screening in ALS patients and controls. We identified three missense variants in  EWSR1  in ALS patients, which were absent in a large number of healthy control individuals. We show that disease-specific variants affect EWSR1 localization in motor neurons. We also provide multiple independent lines of  in vitro  and  in vivo  evidence that EWSR1 has similar properties as TDP-43, FUS and TAF15, including aggregation–prone behavior  in vitro  and ability to confer neurodegeneration in  Drosophila . Postmortem analysis of sporadic ALS cases also revealed cytoplasmic mislocalization of EWSR1. Together, our studies highlight a potential role for EWSR1 in ALS, provide a collection of functional assays to be used to assess roles of additional RNA-binding proteins in disease and support an emerging concept that a class of aggregation–prone RNA-binding proteins might contribute broadly to ALS and related neurodegenerative diseases.

Evaluating the role of the FUS/TLS -related gene EWSR1 in amyotrophic lateral sclerosis