The role of MSUT-2 in tau neurotoxicity: a target for neuroprotection in tauopathy?
We previously developed a transgenic Caenorhabditis elegans model of human tauopathy disorders by expressing human tau in nematode worm neurons to explore genetic pathways contributing to tau-induced neurodegeneration. This animal model recapitulates several hallmarks of human tauopathies, including altered behaviour, accumulation of detergent-insoluble phosphorylated tau protein and neurodegeneration. To identify genes required for tau neurotoxicity, we carried out a forward genetic screen for mutations that suppress tau neurotoxicity. We ultimately cloned the sut-2 (suppressor of tau pathology-2) gene, mutations in which alleviate tau neurotoxicity in C. elegans. SUT-2 encodes a novel subtype of CCCH zinc-finger protein conserved across animal phyla. SUT-2 shares significant identity with the mammalian SUT-2 (MSUT-2). We identified components of the aggresome as binding partners of MSUT-2. Thus we hypothesize that MSUT-2 plays a role in the formation and/or clearance of protein aggregates. We are currently exploring the role of MSUT-2 in tauopathy using mammalian systems. The identification of sut-2 as a gene required for tau neurotoxicity in C. elegans suggests new neuroprotective strategies targeting MSUT-2 that may be effective in modulating tau neurotoxicity in human tauopathy disorders.
Wheeler
Jeanna M
JM
Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, 1660 S Colombian Way, Seattle, WA 98108, USA.
Guthrie
Chris R
CR
Kraemer
Brian C
BC
D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008954:Models, Biological; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; C553363:MSUT-2 protein, human; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D039102:Poly(A)-Binding Proteins; D016601:RNA-Binding Proteins; C541940:SUT-2 protein, C elegans; C522547:ZC3H14 protein, human