Identifying therapeutic peptides for autophagy-mediated degradation of pathogenic protein aggregates

Accumulation of protein aggregates in neuronal cells disrupts their function, leading to neurodegenerative disorders like Alzheimer’s Disease. Methods for targeted degradation of these aggregates have therapeutical potential for delaying disease onset and progression. Therapeutics that target degradation via the proteasome have had clinical success for soluble protein targets but are inefficient for degrading insoluble protein aggregates.

Autophagic and lysosomal degradation pathways are proteasome-independent and degrade protein aggregates efficiently, but methods for targeting substrates to these degradation pathways are limited. This project team will investigate two Proteasome-Independent Targetable (PRINT) Degraders that they have recently identified. The project explores the pathways required for their degradation activity and will establish the activity of these PRINT degraders in degrading tau proteins, which can form neuropathic aggregates, in primary rat neurons. The team will then conduct a high-throughput screen to identify additional PRINT degraders, expanding the therapeutic toolbox for targeted degradation of protein aggregates.

Exploring the degradation activity of these peptides on additional neuropathic aggregates or non-protein substrates (damaged organelles and biomolecular condensates) will define other therapeutic autophagy-targeting chimera (AuTAC) opportunities. Identifying peptides capable of targeted autophagy and demonstrating success in an ex vivo model is critical for this project to be competitive for funding from the NIH’s National Institute of Aging, which is committed to developing therapies for Alzheimer’s disease and other neurodegenerative disorders.

PRINCIPAL INVESTIGATOR

Anjon Audhya, professor of biomolecular chemistry

CO-PRINCIPAL INVESTIGATOR

Gaelen Hess, assistant professor of biomolecular chemistry

CO-INVESTIGATOR

Weiping Tang, professor of pharmaceutical sciences