Other than the recently approved antibody, Aducanumab, which may help early onset patients, there are no therapeutic treatments to prevent, slow or cure neurodegenerative diseases such Alzheimer's disease and related dementias (ADRD). Current treatments only temporarily suppress disease symptoms. This work aims to investigate small molecule 20S proteasome activation as a new, innovative therapeutic strategy to slow and/or prevent disease progression. Proteins such as amyloid-Beta, alpha-synuclein and dipeptide repeat units are intrinsically disordered proteins (IDPs), which have a high tendency to oligomerize and aggregate upon accumulation. The exact mechanism by which these oligomers induce neurotoxicity is complex and still debated. However, it is widely accepted that accumulation of these aggregation-prone proteins results in (1) toxic oligomeric species and (2) proteasome impairment, which are two classic hallmarks of neurodegenerative disorders that ultimately drive disease progression. In this exploratory R21 grant, we are pioneering a new paradigm in drug discovery, which is focused on preventing the accumulation of IDPs by enhancing the activity of the 20S proteasome using small molecules. Our hypothesis is that small molecule 20S proteasome enhancement will induce the degradation of IDPs, and thereby prevent and restore proteasome function, that was impaired by these IDP oligomers. To test this hypothesis, we will explore the efficacy of two new, but distinct classes of 20S proteasome enhancers, discovered and published by our research group, for their ability to (1) prevent IDP accumulation and (2) restore impaired proteasome function. Impact: According to the National Institutes of Aging, AD is the 6th leading cause of death in the US, yet it remains mostly without effective treatment options. Successful completion of this work will validate a new strategy that tackles two fundamental steps in the pathogenesis of these disorders, which may provide a therapeutic strategy to treat these devastating dementias.