Molecular pathways that influence human tau-induced pathology in Caenorhabditis elegans

被引:111
作者
Kraemer, BC
Burgess, JK
Chen, JH
Thomas, JH
Schellenberg, GD
机构
[1] Vet Affairs Puget Sound Hlth Care Syst, Ctr Geriatr Res Educ & Clin, Seattle Div, Seattle, WA 98108 USA
[2] Univ Washington, Dept Med, Div Gerontol & Geriatr Med, Seattle, WA USA
[3] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA
[4] Univ Washington, Dept Neurol, Div Neurogenet, Seattle, WA 98195 USA
[5] Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA
关键词
D O I
10.1093/hmg/ddl067
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations in the gene encoding tau cause frontotemporal dementia with parkinsonism-chromosome 17 type (FTDP-17). In FTDP-17, Alzheimer's disease, and other tauopathies, aggregated hyper-phosphorylated tau forms the neurofibrillary tangles characteristic of these disorders. We previously reported a Caenorhabditis elegans model for tauopathies using human normal and FTDP-17 mutant tau as transgenes. Neuronal transgene expression caused insoluble phosphorylated tau accumulation, neurodegeneration and uncoordinated (Unc) movement. Here we describe a genome-wide RNA-mediated interference (RNAi) screen for genes that modify the tau-induced Unc phenotype. We tested RNAi sequences for 16 757 genes and found 75 that enhanced the transgene-induced Unc phenotype. Forty-six of these genes have sequence similarity to known human genes and fall into a number of broad classes including kinases, chaperones, proteases and phosphatases. The remaining 29 modifiers have sequence similarity only with other nematode genes. To determine if the enhancers are specific for the tau-induced Unc behavior, we exposed several non-tau Unc mutants to tau RNAi enhancer clones. Fifteen enhancers modified phenotypes in multiple Unc mutants, whereas 60 modified only the Unc phenotype in the tau transgenic lines. We also introduced the tau transgene into the background of genetic loss-of-function mutations for a subset of the enhancer genes. Tau transgenic animals homozygous for loss of these enhancer genes exhibited increased impaired motility relative to the tau transgene line alone. This work uncovers novel candidate genes that prevent tau toxicity, as well as genes previously implicated in tau-mediated neurodegeneration.
引用
收藏
页码:1483 / 1496
页数:14
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