Grant: CIHR New Investigator

Protein aggregation is a pathological feature of a large number of diseases with a strong preponderance in age-related neurodegenerative disorders like Huntington's disease. Failure to eliminate aberrant proteins plays a major role in these pathologies and is often linked to the impairment of the ubiquitin proteasome system, which degrades proteins labeled (or modified) with ubiquitin. The overall goal of this proposal is to further define the involvement of this system in aggregation diseases using proteomic and chemical biological approaches. We developed a new assay to monitor the formation of aggregates induced by proteasome inhibition and we identified several new proteins that localize in these structures. We will determine whether these newly identified proteins are also involved in the formation of the aggregates. We also identified several small molecules that perturbed the aggregate formation in the cell and will further characterize them. Current treatments for most aggregation diseases are primarily based on symptom management instead of directly treating the cause. A major endeavor is to identify small molecules that block the cause of the disease progression and identify which cellular pathways are involved in aggregation. Our work may potentially lead to better understanding of aggregation mechanism and identify new targetable pathways to prevent formation or favor clearance of proteins aggregates.