Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY Protein aggregation is associated with both neurodegenerative and systemic diseases such as Alzheimer’s disease, ALS, and Transthyretin amyloidosis. Highly ordered aggregates known as amyloids underlie these disease pathologies. Proteins can also undergo liquid-liquid phase separation to form amorphous aggregates that assemble into biomolecular condensates. Proteins within condensates are dynamic and reversible. However, with age and stress, persistence of proteins within these condensates can lead to solidification and formation of irreversible aggregates associated with disease. Our LONG-TERM GOAL is to understand how cells manage protein aggregates. It is well established that molecular chaperones play a critical role in the disassembly of both condensates and amyloids. However, the field is beginning to unlock the mechanisms in which chaperones mediate this disassembly. Two different chaperone systems have been identified to have “disaggregase” activity. Hsp110 is a highly conserved nucleotide exchange factor that binds with members of the Hsp70 family for disaggregation. The Hsp104 system also binds with the Hsp70 family chaperones to disassemble and fragment protein aggregates. It has been suggested that these two systems may work together to increase disaggregation efficiency. Understanding the mechanisms that underlie this synergy will provide significant leverage into developing therapeutic directions for treating neurodegenerative and systemic protein aggregation diseases. The OBJECTIVE OF THIS PROJECT is to define how Hsp110 and Hsp104 systems work together, whether in parallel or in concert, to manage different types of protein aggregates. Due to strong conservation of chaperone systems across eukaryotic systems, a yeast-based model provides a tractable system for undergraduate researchers to study molecular mechanisms that underlie protein disaggregation. The goal of this proposal is to understand how Hsp104 and Hsp110 chaperone systems manage protein disaggregation using three different protein aggregation systems: A) the study of biomolecular condensates: stress granules, B) the study of human amyloid: Transthyretin protein, and C) the study of a yeast-specific amyloid: [PSI+]. This multi-pronged approach provides the ability for controlled exploration of how these two chaperone systems coordinate their efforts to manage different protein aggregate substrates. This approach will provide important understanding of how chaperone systems efficiently and quickly manage protein aggregates, and how they may be exploited for the treatment of protein aggregation diseases.
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