This $1,823,353 Project Grant awarded by the National Institute on Aging (CFDA 93.866 Aging Research) to the Seattle Institute For Biomedical And Clinical Research aims to elucidate the molecular mechanisms by which pathological tau protein causes neurodegeneration in Alzheimer's disease (AD) and related tauopathy disorders.
The research project will leverage a C. elegans model of tauopathy to investigate the functional role of nuclear speckles, membraneless organelles involved in RNA processing, in modulating tau toxicity. The study will: 1) define how the speckle-resident E3 ubiquitin ligase adaptor protein SPOP impacts neuronal nuclear speckle composition and dynamics in tauopathy, 2) identify critical non-degradative CUL3SPOP E3 ligase ubiquitination substrates participating in tauopathy, and 3) explore the role of these substrates in human disease and mouse models of tauopathy. This work aims to provide new molecular insights into how nuclear speckles and the SPOP protein contribute to tau-mediated neurodegeneration, and explore whether targeting these processes could protect neurons from pathological tau in the mammalian brain.
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