Intrinsically disordered proteins (IDPs) are proteins that lack a defined tertiary structure in their native cellular environment. The 20S proteasome is charged with regulating cellular levels of these proteins, but this pathway can become dysregulated leading to IDP accumulation. Accumulation and aggregation of some IDPs (α-synuclein, tau, amyloid beta, etc.) has been shown to be associated with the pathogenesis of several neurodegenerative diseases (Parkinson’s disease, Alzheimer’s disease). Although the mechanisms for their pathogenesis are still under investigation, it has been shown that oligomeric forms of some of these IDPs can cause inhibition of the proteasome and cellular toxicity. This leads to further accumulation of IDPs and other damaged proteins promoting progression of these diseases. The Tepe Lab aims to develop small molecule activators of the 20S proteasome that enhance its ability to degrade IDPs and prevent further accumulation and aggregation. We propose that proteasome activators represent a novel therapeutic method by which we may impede neurodegenerative disease progression. Here, I present novel activators that show strong 20S proteasome enhancement and potential for helping to overcome the burden of accumulated IDPs and inhibitory oligomeric species. Additionally, I propose that 20S proteasome activation may allow for protection against IDP related toxicities by degrading and/or preventing the formation of toxic IDP species.

20S proteasome activators enhance degradation of intrinsically disordered proteins associated with neurodegeneration and protect against inhibitory oligomers

ACS Spring 2022

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