20S Proteasome Activation as an Innovative Therapeutic Strategy

Presented by Taylor Martinez-Fiolek, Department of Chemistry, Michigan State University

• Monday, March 20th, 2023
• 4 - 5 p.m. in Dow 175

Oligomerization of aggregation-prone intrinsically disordered proteins, such as a-synuclein, amyloid p and tau, has been shown to be associated with the pathogenesis of several neurodegenerative diseases, including Parkinson's and Alzheimer's disease.

The 20S proteasome is charged with regulating cellular levels of IDPs, but this degradation pathway can become dysregulated leading to their accumulation and aggregation. Although the pathogenesis of these neurodegenerative diseases is still under intense investigation, it has been shown that the oligomeric forms of IDPs can impair proteasome function. This leads to additional accumulation of the I DPs, further promoting disease progression.

The Tepe Lab aims to develop small molecule activators of the 20S proteasome that enhance its ability to degrade I DPs and prevent their further accumulation and aggregation. We propose that proteasome activators represent a novel therapeutic method by which we may impede neurodegenerative disease progression. Here, I report the identification of novel small molecule activators of the 20S proteasome and demonstrate for the first time that they have the potential to protect against inhibition of the 20S proteasome by IDP oligomers and begin to restore protein homeostasis.