title: Reduction of polyglutamine toxicity by TDP-43, FUS and progranulin in Huntington's disease models.
abstract: The DNA/RNA binding proteins TAR DNA-binding protein 43 (TDP-43) and fused-in-sarcoma (FUS) are genetically linked to amyotrophic lateral sclerosis and frontotemporal lobar dementia, while the inappropriate cytoplasmic accumulations of TDP-43 and FUS are observed in a growing number of late-onset pathologies including spinocerebellar ataxia 3, Alzheimer's and Huntington's diseases (HD). To investigate if TDP-43 and FUS contribute to neurodegenerative phenotypes, we turned to a genetically accessible Caenorhabditis elegans model of polyglutamine toxicity. In C. elegans, we observe that genetic loss-of-function mutations for nematode orthologs of TDP-43 or FUS reduced behavioral defects and neurodegeneration caused by huntingtin exon-1 with expanded polyglutamines. Furthermore, using striatal cells from huntingtin knock-in mice we observed that small interfering ribonucleic acid (siRNA) against TDP-43 or FUS reduced cell death caused by mutant huntingtin. Moreover, we found that TDP-43 and the survival factor progranulin (PGRN) genetically interact to regulate polyglutamine toxicity in C. elegans and mammalian cells. Altogether our data point towards a conserved function for TDP-43 and FUS in promoting polyglutamine toxicity and that delivery of PGRN may have therapeutic benefits.
authors.affiliation: CRCHUM, Université de Montré al, Montréal, Québec, Canada.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Tauffenberger
authors.forename: Babykumari P
authors.initials: BP
authors.lastname: Chitramuthu
authors.forename: Andrew
authors.initials: A
authors.lastname: Bateman
authors.forename: Hugh P J
authors.initials: HP
authors.lastname: Bennett
authors.forename: J Alex
authors.initials: JA
authors.lastname: Parker
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000473:pathology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D000077155:Granulins; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D000077153:Progranulins; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D000077155:Granulins; D006655:Histone Deacetylases; D000071058:Huntingtin Protein; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D000077153:Progranulins; D034741:RNA, Small Interfering; C120204:Grn protein, mouse; C506812:Htt protein, mouse; C578077:Tardbp protein, mouse; C097188:polyglutamine