RRC ID |
21111
|
著者 |
Tauffenberger A, Chitramuthu BP, Bateman A, Bennett HP, Parker JA.
|
タイトル |
Reduction of polyglutamine toxicity by TDP-43, FUS and progranulin in Huntington's disease models.
|
ジャーナル |
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.
|
巻・号 |
22(4)
|
ページ |
782-94
|
公開日 |
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
|
引用数 |
21
|
WOS 分野
|
GENETICS & HEREDITY
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
リソース情報 |
線虫 |
fust-1(tm4439)
pgrn-1(tm985) |