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.