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Domain-specific Changes in Chip Function Explain Distinct Clinical Features in Sca48 Patients

Year: 2025
Type: dissertation
Abstract: Protein quality control (PQC) is one of the essential cellular mechanisms that ensures proper cellular function by maintaining protein homeostasis during various stressors. Molecular chaperones along with their co-chaperones, play a crucial role in PQC by regulating the balance between protein folding and degradation of terminally misfolded or aggregated proteins. This delicate equilibrium in protein triage is achieved through direct interactions between chaperones and different co-chaperones. Co-chaperones influence the fate of protein triage by modifying the chaperone function, either facilitating protein folding or promoting protein degradation. Disruption of chaperone/co-chaperone interactions due to coding mutations, post-translational modifications, and changes in gene expression is implicated in multiple diseases. In this dissertation, we investigated the role of carboxyl terminus of Hsc70-interacting protein (CHIP), a co-chaperone that regulates both protein folding and degradation pathways, in two neurodegenerative diseases. In Chapter 2, we performed a comprehensive characterization of the changes that occur in CHIP function with mutations identified in spinocerebellar ataxia 48 (SCA48), a progressive neurodegenerative disease that affect the cerebellum and presents various clinical symptoms. We showed how SCA48 mutations alter steady-state levels and solubility of CHIP protein. Additionally, we identified mutation location-specific functional changes in CHIP, including loss of substrate ubiquitination and co-chaperone activity. Importantly, we demonstrated a correlation between domain-specific functional changes and certain clinical symptoms observed in SCA48 patients. In Chapter 3, we identified a novel role of CHIP in regulating stress granules (SG) in Alzheimer’s Disease (AD). We discovered novel interactions between CHIP and core proteins of SG. Furthermore, we showed that CHIP’s ubiquitin ligase activity plays a protective role against SG-mediated tau aggregation in cells expressing the wild type tau. Moreover, we demonstrated that this protective effect was abolished when an aggregate prone tau variant was expressed. Altogether, the findings presented in this dissertation enhance our understanding of how disruptions in specific functions of CHIP are linked to the disease phenotypes observed in SCA48 patients. Moreover, our research uncovered a novel role for CHIP, highlighting its involvement in the pathogenesis of neurodegenerative diseases.
DOI: 10.17615/a9vj-kv28
Language: English
Open Access status: green
OpenAlex ID: W7077479634
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