title: TDP-43 suppresses CGG repeat-induced neurotoxicity through interactions with HnRNP A2/B1.
abstract: Nucleotide repeat expansions can elicit neurodegeneration as RNA by sequestering specific RNA-binding proteins, preventing them from performing their normal functions. Conversely, mutations in RNA-binding proteins can trigger neurodegeneration at least partly by altering RNA metabolism. In Fragile X-associated tremor/ataxia syndrome (FXTAS), a CGG repeat expansion in the 5'UTR of the fragile X gene (FMR1) leads to progressive neurodegeneration in patients and CGG repeats in isolation elicit toxicity in Drosophila and other animal models. Here, we identify the amyotrophic lateral sclerosis (ALS)-associated RNA-binding protein TAR DNA-binding protein (TDP-43) as a suppressor of CGG repeat-induced toxicity in a Drosophila model of FXTAS. The rescue appears specific to TDP-43, as co-expression of another ALS-associated RNA-binding protein, FUS, exacerbates the toxic effects of CGG repeats. Suppression of CGG RNA toxicity was abrogated by disease-associated mutations in TDP-43. TDP-43 does not co-localize with CGG RNA foci and its ability to bind RNA is not required for rescue. TDP-43-dependent rescue does, however, require fly hnRNP A2/B1 homologues Hrb87F and Hrb98DE. Deletions in the C-terminal domain of TDP-43 that preclude interactions with hnRNP A2/B1 abolish TDP-43-dependent rescue of CGG repeat toxicity. In contrast, suppression of CGG repeat toxicity by hnRNP A2/B1 is not affected by RNAi-mediated knockdown of the fly TDP-43 orthologue, TBPH. Lastly, TDP-43 suppresses CGG repeat-triggered mis-splicing of an hnRNP A2/B1-targeted transcript. These data support a model in which TDP-43 suppresses CGG-mediated toxicity through interactions with hnRNP A2/B1 and suggest a convergence of pathogenic cascades between repeat expansion disorders and RNA-binding proteins implicated in neurodegenerative disease.
authors.affiliation: Department of Neurology, University of Michigan Medical School, 109 Zina Pitcher Pl, Ann Arbor, MI 48109, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Neurology, University of Michigan Medical School, 109 Zina Pitcher Pl, Ann Arbor, MI 48109, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Krans
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA and.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Freibaum
authors.affiliation: Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, TN 38105, USA and.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Department of Neurology, University of Michigan Medical School, 109 Zina Pitcher Pl, Ann Arbor, MI 48109, USA, VA Medical Center, Ann Arbor, MI 48105, USA petertod@umich.edu.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Todd
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D030801:Animals, Genetically Modified; D001259:Ataxia / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005123:Eye / Q000254:growth & development / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D036081:Receptors, Eph Family / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014202:Tremor / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C000589036:TBPH protein, Drosophila; D036081:Receptors, Eph Family