Human Molecular Genetics Advance Access published online on April 6, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl067
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1 Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, WA.; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington
* To whom correspondence should be addressed. Mutations in the gene encoding tau cause frontotemporal dementia with parkinsonism - chromosome 17 type (FTDP-17). In FTDP-17, Alzheimer's disease (AD), and other tauopathies, aggregated hyper-phosphorylated tau forms the neurofibrillary tangles characteristic of these disorders. We previously reported a C. 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, while 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.
Received January 7, 2006
Revised March 16, 2006
Accepted March 16, 2006
Article
Molecular pathways that influence human tau-induced pathology in C. elegans
Brian C. Kraemer 1,
Jack K. Burgess 1,
Jin H. Chen 1,
James H. Thomas 2,
and
Gerard D. Schellenberg 3 *
2 Department of Genome Sciences, University of Washington, Seattle WA
3 Associate Director for Research, Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division 1660 S. Columbian Ave., Seattle, WA, 98108-1597; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington; Division of Neurogenetics, Department of Neurology, University of Washington, Seattle WA; Department of Pharmacology, University of Washington, Seattle WA
Gerard D. Schellenberg, E-mail: zachdad{at}u.washington.edu
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