RRC ID 21111
Author Tauffenberger A, Chitramuthu BP, Bateman A, Bennett HP, Parker JA.
Title Reduction of polyglutamine toxicity by TDP-43, FUS and progranulin in Huntington's disease models.
Journal Hum Mol Genet
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.
Volume 22(4)
Pages 782-94
Published 2013-2-15
DOI 10.1093/hmg/dds485
PII dds485
PMID 23172908
MeSH Animals Animals, Genetically Modified Axons / pathology Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cell Line DNA-Binding Proteins / genetics DNA-Binding Proteins / metabolism* Disease Models, Animal Gene Knockdown Techniques Granulins Histone Deacetylases / metabolism Humans Huntingtin Protein Huntington Disease / metabolism* Huntington Disease / pathology Intercellular Signaling Peptides and Proteins / genetics Intercellular Signaling Peptides and Proteins / metabolism* Male Mice Nerve Tissue Proteins / genetics Nerve Tissue Proteins / metabolism* Nuclear Proteins / genetics Nuclear Proteins / metabolism* Peptides / genetics Peptides / metabolism* Progranulins RNA, Small Interfering / genetics
IF 5.101
Times Cited 21
C.elegans fust-1(tm4439) pgrn-1(tm985)