SPOP drives neurodegenerative tauopathy

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Abstract: Aggregated pathological tau protein constitutes one of the diagnostic hallmarks of Alzheimer’s disease (AD) and related disorders (ADRD). The molecular mechanisms by which pathological tau causes dysfunction and degeneration of neurons remains incompletely understood. However, pathological tau driven neuronal dysfunction and neurodegeneration clearly cause dementia. To investigate how pathological tau contributes to neurodegeneration in AD and ADRD, we established a transgenic model in C. elegans for neurodegeneration driven by human tau aggregation. In our previous work, we identified several genes that control tau toxicity in C. elegans including sut-1, sut-2, parn-2, sut-6, aly-1, aly-2, and aly-3; all of these genes share the common property of encoding proteins residing within nuclear speckles. Nuclear speckles are membraneless organelles within the cell’s nucleus that function as hubs of RNA processing. Previous translational work from our laboratory and others have shown that AD/ADRD exhibit defects in RNA processing and mislocalization of several nuclear speckle proteins including MSUT2, PABPN1, and SRRM2. We have leveraged our C. elegans model of tauopathy to begin to dissect the functional role of nuclear speckles in tau pathology. We found tau mediated neuronal dysfunction and neurodegeneration can be rescued by loss of a nuclear speckle resident E3 ubiquitin ligase adaptor protein known as SPOP. We hypothesize SPOP-mediated degradation of substrate proteins impacts the dynamics and liquid-liquid phase separation of nuclear speckles to modulate the toxicity of pathological tau. Given the high level of conservation of the nuclear speckle proteins and RNA processing system between mammals and C. elegans, we propose to utilize both C. elegans and mouse transgenic tauopathy models to dissect the molecular mechanisms by which SPOP loss of function protects against tau neurotoxicity. The Specific Aims of this project are to: 1) Define SPOP’s impact on neuronal nuclear speckle composition and dynamics in tauopathy. 2) Identify critical non-degradative CUL3SPOP E3 ligase ubiquitination substrate(s) participating in tauopathy. 3) Explore the role of critical CUL3SPOP substrate proteins in both human disease and mouse models of tauopathy. By completing the proposed work, we will develop new molecular understanding of disease mechanisms by which nuclear speckles and the SPOP protein participate in tauopathy. This work will also provide the first translational effort at understanding whether targeted changes in nuclear speckles can protect neurons from pathological tau in the mammalian brain.