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Resources » Paper

Kraemer BC et al. (2006) Hum Mol Genet "Molecular pathways that influence human tau-induced pathology in Caenorhabditis elegans."

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  • Comments on Kraemer BC et al. (2006) Hum Mol Genet "Molecular pathways that influence human tau-induced pathology in Caenorhabditis elegans." (0)

  • Overview

    PMID:
    16600994
    DOI:
    10.1093/hmg/ddl067
    Status:
    Publication type:
    Journal_article
    WormBase ID:
    WBPaper00027214

    Kraemer BC, Burgess JK, Chen JH, Thomas JH, & Schellenberg GD (2006). Molecular pathways that influence human tau-induced pathology in Caenorhabditis elegans. Hum Mol Genet, 15, 1483-96. doi:10.1093/hmg/ddl067

    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.


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