Development of a Parkin Based Autophagy-Targeting Chimera

Ian Horsburgh
Jane Liu, Pomona College
Tsui-Fen Chou, California Institute of Technology

Abstract

Misfolded protein aggregation is the hallmark of neurodegenerative disease, causing neuron damage and eventual death. While current treatments focus on stimulating weakened neurons, emerging therapies aim to act upstream by preventing aggregation or degrading aggregates once formed. One approach to this degradation strategy is to repurpose the mitochondrial control mechanism of autophagy to engulf and degrade the damaged aggregates via the lysosome. In this mitochondrial quality control mechanism, the activation and localization of the protein Parkin to the mitochondria plays a key role in autophagy initiation. We aim to provide proof of concept that a heterobifunctional small molecule capable of recapitulating this activation and localization mechanism could induce substrate degradation.