Protein aggregation controlled by disaggregases.

Our lab aims to deepen the understanding of the molecules and mechanisms that drive protein aggregation. We approach this by studying protein aggregation catalysis and inhibition through biological disaggregases, including macromolecular chaperones, proteasomes, and metabolites. Our recent findings suggest that disaggregase activity operates on a continuum, with protein aggregation catalysis and inhibition at opposite ends of the spectrum. Bimodal effects on protein aggregation are a defining characteristic of disaggregases. The disaggregase mechanism, characteristic of macromolecular chaperones, generates fragmented fibrils, oligomers, and monomeric proteins in varying proportions, which seed protein aggregation. Although seeding is primarily associated with disease, bimodal effects by disaggregases on seeding suggests disaggregases might toggle aggregation, regulating protein activity by switching it on and off depending on concentrations and relevant cofactors. However, the extent to which the same disaggregases can function both as inhibitors and aggregation catalysts under different conditions to regulate protein activity remains unclear. Our lab will explore the biological implications of disaggregases in reversibly regulating protein function. We hypothesize that disaggregases generating intermediate species, such as oligomers and fragmented fibrils, promote aggregation by creating seeding-competent nuclei, which inactivate proteins by sequestering them in aggregates. We anticipate that shifting disaggregase concentrations to favor aggregate elimination will restore the activity of functional proteins. Our future objectives include bioinformatic, biochemical, and cellular studies to uncover the molecular determinants of disaggregase activity and identify new biological disaggregases in the human metabolome. By elucidating the factors involved in both protein aggregation catalysis and disaggregase efficacy, our work will reveal disaggregases that can reversibly control protein aggregation. This foundational research will guide our lab’s ongoing efforts to unravel the etiology of protein misfolding and develop diagnostics and therapeutics for protein aggregation diseases. Project Number: 1R35GM160152-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Paul Seidler | Institution: UNIVERSITY OF SOUTHERN CALIFORNIA, Los Angeles, CA | Award Amount: $2,282,500 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award B Study Section[MRAB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11202791