PROJECT SUMMARY A growing number of Americans over the age of 65 live with dementia. A set of devastating neurodegenerative diseases cause dementia, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Neurofibrillary tangles composed of hyperphosphorylated tau are a pathological hallmark of AD and related tauopathy disorders including FTLD-tau. Several other pathologies also drive neurodegeneration in AD related dementias (ADRD), including the aggregation of the RNA binding protein TDP-43 and expansion-related polyglutamine repeat proteins (PolyQ). While the ultimate molecular mechanisms driving neurodegeneration in AD/ADRD are poorly understood, disruptions to many aspects of nuclear homeostasis in neurons contribute to these age-related diseases, including disruptions to nuclear pore complexes, nucleocytoplasmic transport and, as I have helped to show, nuclear speckles and RNA processing. My published work and preliminary data now also nominate nuclear proteostasis and nuclear ubiquitin proteasome system (UPS) machinery as novel and shared regulators of the early pathogenesis of neurotoxic aggregates and neurodegeneration in AD, FTLD, and Huntington’s disease, an inherited early-onset dementia. I previously showed that genetic deletion of SPOP homolog SPOP-1 rescues significant behavioral deficits, protein aggregation, lifespan defects, and neurodegeneration driven by the microtubule-binding protein tau in a Caenorhabditis elegans model of tauopathy. My preliminary evidence suggests that the activity of C. elegans SPOP-1/CUL-3 nuclear substrate BET-2, homologous to the bromodomain and extraterminal domain (BET) family of transcription factor proteins in humans (BRD2, BRD3, BRD4, and BRDT), underlie these results. My early data also show SPOP modifies TDP-43 and PolyQ neurotoxicity in models of AD/ADRD proteinopathy and is translationally relevant in mammalian neurons and to human disease. Altogether, my work has led us to hypothesize that the degradation of BRD transcription factors is a critical and translationally relevant molecular pathway to neurodegeneration in AD/ADRD. We hypothesize disruptions to nuclear UPS machinery and nuclear proteostasis, in general, are also key contributors to nuclear dysfunction in early disease pathogenesis. To investigate these hypothesizes the specific aims of this project are: SPECIFIC AIMS: (1) Determine the impact and relevance of BRD transcription factor degradation in AD/ADRD. (2) Systematically characterize the impact of nuclear proteostasis machinery in AD/ADRD. By completing the proposed work, we will provide further insight into the biological mechanisms underlying the role of the CUL3/SPOP/BRD axis (F99) and, more broadly, the role of disruptions to nuclear protein homeostasis (K00) in driving neurodegeneration in AD and diverse ADRDs.