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• W4313251117 abstract "The pathological accumulation of the microtubule binding protein tau drives age-related neurodegeneration in a variety of disorders, collectively called tauopathies. In the most common tauopathy, Alzheimer's disease (AD), the accumulation of pathological tau strongly correlates with cognitive decline. The underlying molecular mechanisms that drive neurodegeneration in tauopathies remain incompletely understood and no effective disease modifying pharmacological interventions currently exist. Here, we show that tau toxicity depends on the highly conserved nuclear E3 ubiquitin ligase adaptor protein SPOP in a Caenorhabditis elegans model of tauopathy. Loss of function mutations in the C. elegans spop-1 gene significantly improves behavioral deficits in tau transgenic animals, while neuronal overexpression of SPOP-1 protein significantly worsens behavioral deficits. In addition, loss of spop-1 rescues a variety of tau-related phenotypes including the accumulation of total and phosphorylated tau protein, neurodegeneration, and shortened lifespan. Knockdown of SPOP-1's E3 ubiquitin ligase cul-3/Cullin3 does not improve tauopathy suggesting a non-degradative mechanism of action for SPOP-1. Suppression of disease-related phenotypes occurs independently of the nuclear speckle resident poly(A)-binding protein SUT-2/MSUT2. MSUT2 modifies tauopathy in mammalian neurons and in AD. Our work identifies SPOP as a novel modifier of tauopathy and a conceptual pathway for therapeutic intervention." @default.
• W4313251117 created "2023-01-06" @default.
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• W4313251117 date "2022-12-27" @default.
• W4313251117 modified "2023-09-26" @default.
• W4313251117 title "SPOP loss of function protects against tauopathy" @default.
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• W4313251117 doi "https://doi.org/10.1073/pnas.2207250120" @default.
• W4313251117 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36574656" @default.
• W4313251117 hasPublicationYear "2022" @default.
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