Grant: Project Grant

Age-related diseases are a growing medical challenge for an aging population. These include neurodegenerative diseases which have no known cure, such as Parkinson disease and amyotrophic lateral sclerosis (ALS), and which are characterized by the accumulation of insoluble protein aggregates. Normally folded proteins can become damaged by mutation or stress, leading to misfolding and aggregation. The chaperone proteins are critical cellular defenses against aggregation. They bind misfolded proteins to promote folding, or help remove permanently damaged proteins by degradation. Nevertheless, damaged proteins build up during aging and are thought to overwhelm the chaperones. Hsp70 is one of the most important chaperones, as it has key roles in protein folding and prevention of aggregation. The different functions of Hsp70 are determined by its regulatory co-chaperone proteins. Recently, another role of Hsp70 was found, in the solubilization of proteins out of aggregates. We propose that disaggregation of proteins is an important pathway for their degradation by proteasomes, which may have an advantage over the slower degradation of aggregates by autophagy. We will examine Hsp70-mediated disaggregation using purified proteins and in live cells, to determine its biochemical mechanisms. A focus will be the co-chaperones and chaperones required for disaggregation. Next, we will address the importance of disaggregation and proteasomal degradation in models of ALS, caused by mutations in the SOD1 protein leading to its aggregation. We will then address other cellular proteins that are at risk of aggregation when the Hsp70 system is impaired. Post-translational modifications on Hsp70 that regulate its function under different stress conditions will be identified. Our project will explore how Hsp70 acts and fails in protein aggregation diseases, and the possibility of enhancing its function towards future therapies.