Leveraging Protein Homeostasis as a Disease-modifying Strategy

Abstract

Protein homeostasis (proteostasis) is a fundamental determinant of cellular health, and its impairment is causally linked to a wide range of human diseases. While extensive eHort has gone into characterising how the proteostasis network (PN) maintains proteins in their functional states, more work is needed to uncover the complex proteostasis mechanisms that are particularly vulnerable to collapse in disease. To address this problem, bioinformatics approaches were deployed to investigate the links between proteostasis and disease. By coupling bioinformatic predictions with cell-based experimental techniques, the components of the PN more closely associated with pathological processes in disease were quantitatively determined. A large-scale pan-disease analysis of patient omics data revealed distinct proteostasis signatures representative of unique disease groups, reflecting diHerences proteostasis implication in early in Cancer and progressively in neurodegenerative conditions. Delving deeper into specific diseases, we use protein-protein interaction data to demonstrate an intersection between Aβ and tau PNs and carry out cell-based experiments to propose this indirect connection as a potentially novel mechanism connecting Aβ and tau hyperphosphorylation in Alzheimer’s disease. Additionally, comparisons of α-synuclein PN protein expressions lend support to the threshold theory in predicting regional vulnerability in the brain of Parkinson’s patients. Extending this work toward the understanding of proteostasis in regulating protein assembly through protein phase separation (PPS), we exemplify that co- chaperones can enable specificity in the formation of membraneless organelles formed via PPS. Based on this, we develop a method for predicting potential substrate-specific modulators of PPS targets in disease and apply it toward a proposed AD PPS target CAMKK2. Together, our findings contribute to a deeper understanding of how proteostasis proteins are involved in disease mechanisms, laying the groundwork for the development of therapeutic strategies aimed at restoring proteostasis as a means of disease intervention.