On the Degradability of Protein Aggregates by Autophagy

forthcoming

"The removal of misfolded and aggregated proteins is essential for cellular homeostasis and organismal health. The accumulation of protein aggregates is associated with several devastating neurodegenerative diseases including Alzheimer’s disease. It has been generally assumed that autophagy has the ability to degrade large aggregates, and considerable efforts are underway to harness this pathway to remove disease-associated aggregates for therapy. However, it is becoming clear that large, solid protein aggregates are poor substrates for autophagy. This is a fundamental conundrum in the basic biology of autophagy, and has posed a serious practical obstacle to these therapeutic efforts. We have obtained data showing that unlike dynamic, liquid-like autophagy targets, rigid solid aggregates can lock the autophagy machinery into non-productive states. Our data also suggest that there are mechanisms whereby these ""stuck"" states can be avoided or reversed. Thus, the autophagy machinery may contain inherent error correction mechanisms, preventing these states. We will seek such mechanisms and characterize them in enough mechanistic detail to make them actionable therapeutically. Enhancing such mechanisms could enable the clearance of aggregates in aging and the most intractable aging-associated diseases. DegrAbility will unite complimentary expertise in cellular engineering, in vitro reconstitution and cutting-edge cryo-EM to identify the requirements for cargo to be effectively degraded by autophagy. The project will pinpoint the vulnerabilities of the autophagy machinery and explore ways to address them. We will explore how the dynamic nature of cellular assemblies, like phase-separated condensates, allows for productive machinery assembly, offering new insights into selective autophagy and cell biology in general. Ultimately, this could be a game changer for mechanism-based disease-modifying therapies for the major aging-associated neurodegenerative diseases."