Abstract. Currently there are limited therapeutic treatments to slow, prevent, or cure neurodegenerative diseases such as Alzheimer’s Disease or Alzheimer’s-related Dementias. Instead, most therapies rely on managing symptoms. These neurodegenerative diseases are characterized by accumulation of intrinsically disordered proteins (IDPs) and impairment of proteasome-mediated protein degradation. This R36 proposal aims to investigate small molecule 20S proteasome activation as a novel strategy to resolve both pathogenic events. Our group has identified fluspirilene and N-acyl-fluspirilene as a novel class of small molecules that not only activate the 20S proteasome to degrade IDPs, but also overcome IDP-induced proteasome impairment. The overarching aims of this project are to (1) identify the mechanism by which the N-acyl-fluspirilene class selectively enhances 20S proteasome activity, and (2) develop enhanced small molecule activators of the 20S proteasome. Successful completion of this work will enable the rapid design, development, and identification of 20S proteasome activators, and elucidate the role of 20S proteasome modulation in neurodegenerative diseases as a novel therapeutic strategy for disease treatment.

Neurodegenerative diseases, including Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD) are characterized by accumulation of intrinsically disordered proteins (IDPs) and impairment of proteasome-mediated protein degradation. This R36 proposal aims to investigate small molecule 20S proteasome activation as a novel strategy to resolve both pathogenic events. Successful completion of this work will enable the rapid design, development, and identification of 20S proteasome activators, and elucidate the role of 20S proteasome modulation in neurodegenerative diseases as a novel therapeutic strategy for disease treatment.