title: Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis.
abstract: Fused in sarcoma (FUS) is mutated in both sporadic amyotrophic lateral sclerosis (ALS) and familial ALS patients. The mechanisms underlying neurodegeneration are not fully understood, but FUS redistributes from the nucleus to the cytoplasm in affected motor neurons, where it triggers endoplasmic reticulum (ER) stress. Ataxin-2 is a polyglutamine protein which normally contains 22 repeats, but expanded repeats (>34) are found in Spinocerebellar Ataxia type 2. Recently ataxin-2 with intermediate length repeats (27-33) was found to increase the risk of ALS. Here we show that ataxin-2 with an ALS-linked intermediate length repeat (Q31) is a potent modifier of FUS pathology in cellular disease models. Translocation of FUS to the cytoplasm and ER stress were significantly enhanced by co-expression of mutant FUS with ataxin-2 Q31. Ataxin-2 also co-localized with FUS in sporadic and FUS-linked familial ALS patient motor neurons, co-precipitated with FUS in ALS spinal cord lysates, and co-localized with FUS in the ER-Golgi compartments in neuronal cell lines. Fragmentation of the Golgi apparatus is linked to neurodegeneration in ALS and here we show that Golgi fragmentation is induced in cells expressing mutant FUS. Moreover, Golgi fragmentation was enhanced, and the early stages of apoptosis were triggered, when ataxin-2 Q31 was co-expressed with mutant FUS. These findings describe new cellular mechanisms linking ALS with ataxin-2 intermediate length polyQ expansions and provide further evidence linking disruption to ER-Golgi compartments and FUS pathology in ALS.
authors.affiliation: Department of Biochemistry, La Trobe University, Vic., Australia.
authors.forename: Manal A
authors.initials: MA
authors.lastname: Farg
authors.forename: Kai Y
authors.initials: KY
authors.lastname: Soo
authors.forename: Sadaf T
authors.initials: ST
authors.lastname: Warraich
authors.forename: Vinod
authors.initials: V
authors.lastname: Sundaramoorthy
authors.forename: Ian P
authors.initials: IP
authors.lastname: Blair
authors.forename: Julie D
authors.initials: JD
authors.lastname: Atkin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D000067528:Ataxins; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D003593:Cytoplasm / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D019680:Trinucleotide Repeat Expansion; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000067528:Ataxins; C494826:BAX protein, human; D009419:Nerve Tissue Proteins; D010455:Peptides; D034702:RNA-Binding Protein FUS; D051028:bcl-2-Associated X Protein; C097188:polyglutamine