Functional And Multi-Omics Approaches To Elucidate The Regulation Of Proteasome Complex In Neurodegenerative Diseases - A hallmark feature of neurodegenerative diseases (NDs) is the accumulation and aggregation of disease-specific proteins in distinct brain regions, leading to cellular dysfunction, loss of synaptic connections, and degeneration. Often ignored nonetheless, a major component of all aggregates is ubiquitin, implicating that dysregulated ubiquitin-proteasome mediated degradation is either a consequence of the disease pathogenesis or that maladaptive proteasomal degradation is one of the common drivers of NDs. In Alzheimer's disease (AD), neurofibliraly tangles (NFT) and neuritic plaques (NP) are decorated with ubiquitin, and a wildly held belief but not rigorously tested is that tau aggregates impede proteolysis, causing a build-up of ubiquitinated inclusion. Historically, this hypothesis has placed the proteasome-mediated proteolysis dysfunction in AD distal to the disease pathogenesis. As a result, the field has shown little interest in the potential role of the proteasome in determining the overall output of the ubiquitin-proteasome system (UPS) in Alzheimer’s and other NDs. However, recent studies in the field recognize proteasome as a fundamental component of the regulation of the UPS and protein homeostasis and that proteasome’s (dys)regulated levels and activity could predict the outcome of protein build-up in AD and other NDs. While functional changes in the proteasome machinery may constitute a common contributing factor to the pathogenesis of NDs, this co-occurring pathology across diseases, in the past, has been studied in isolation from one another. Using integrated multi-omics approaches combined with biochemical and functional approaches proposed in Aim 1 and 2, this application will investigate how the UPS, specifically the proteasome complexes, are affected in AD (in early and late stages), Progressive Supranuclear Palsy (PSP), Parkinson’s, and Amyloid Lateral Sclerosis (ALS) and elucidate a possible shared mechanistic cascade of the failed protein breakdown by the 26S proteasome across clinically diverse NDs. Focusing primarily on AD pathogenesis as a representative disease, Aim 3 will interrogate the negative and positive regulation of the NFE2L/Nrf1, a master transcript factor of the proteasome genes, to uncover the role of Nrf1-mediated proteolysis in AD-afflicted brains, and propose a translational approach of proteasome-targeting intervention that could overcome proteasome impairment and protein aggregation in AD.
