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

Abstract

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.

TheC. elegansperoxidasin PXN-2 is essential for embryonic morphogenesis and inhibits adult axon regeneration

“…PXN-1 could play an analogous regulatory role in the C. elegans matrix. Intriguingly, loss of pxn-1 function can enhance neurodegenerative phenotypes caused by overexpression of the microtubule-binding protein tau (MAPT) in C. elegans, implying that PXN-1 protects against neurodegeneration (Kraemer et al, 2006). Further work will be required to determine whether the neuroprotective effects of PXN-1 are related to its role in regulating the ECM.…”

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

“…In addition, the pathology induced by overexpression of mtHtt in mammalian cells or in C. elegans depends on the mitochondrial fission machinery (8); ced-3 function is also required in C. elegans (56). Lastly, coq-1 RNAi in C. elegans enhances the toxicity of a mutant form of human tau that has been implicated in the pathology of AD (57). It is striking that salient features of these human genetic diseases including selective neuron sensitivity, mitochondrial dysfunction, Ca 2+ dependence, and aberrant cell death (58,59) are observed in C. elegans with the depletion of CoQ.…”

Genetic Modifiers of Neurological Disease

“…Transgenic models recapitulating a feature of the human disease process have been used for modifier screens. Protein misfolding models in C.elegans have been used for genome-wide screens to identify modifiers of α-synuclein inclusion formation, tau-induced pathology, polyglutamine aggregation, and mutant SOD1 aggregation [38][39][40][41]. Yeast models have been used to screen for modifiers of toxicity due to α-synuclein and huntingtin misfolding [42][43][44][45].…”