title: Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis.
abstract: 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.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Couthouis
authors.forename: Michael P
authors.initials: MP
authors.lastname: Hart
authors.forename: Renske
authors.initials: R
authors.lastname: Erion
authors.forename: Oliver D
authors.initials: OD
authors.lastname: King
authors.forename: Zamia
authors.initials: Z
authors.lastname: Diaz
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakaya
authors.forename: Fadia
authors.initials: F
authors.lastname: Ibrahim
authors.forename: Hyung-Jun
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jelena
authors.initials: J
authors.lastname: Mojsilovic-Petrovic
authors.forename: Saarene
authors.initials: S
authors.lastname: Panossian
authors.forename: Cecilia E
authors.initials: CE
authors.lastname: Kim
authors.forename: Edward C
authors.initials: EC
authors.lastname: Frackelton
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Solski
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Williams
authors.forename: Dana
authors.initials: D
authors.lastname: Clay-Falcone
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.forename: Leo
authors.initials: L
authors.lastname: McCluskey
authors.forename: Robert
authors.initials: R
authors.lastname: Greene
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kalb
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
authors.forename: Ian P
authors.initials: IP
authors.lastname: Blair
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Bonini
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.forename: Zissimos
authors.initials: Z
authors.lastname: Mourelatos
authors.forename: James
authors.initials: J
authors.lastname: Shorter
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D002148:Calmodulin-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004330:Drosophila / Q000235:genetics; D005260:Female; D005809:Genes, Regulator; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D020125:Mutation, Missense; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D002148:Calmodulin-Binding Proteins; D004268:DNA-Binding Proteins; C500986:EWSR1 protein, human; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; C102041:TAF15 protein, human; D035381:TATA-Binding Protein Associated Factors