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Protein aggregates formation is a common characteristic of many neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Effective clearance of those toxic protein aggregates is critical for neuronal survival. Aggresome is a newly defined cytoplasmic structure, which serves to sequester accumulated protein aggregates for further degradation. However, the mechanism of aggresome formation is poorly understood. In this study, we discover that 14-3-3 has a general role in promoting aggresome formation. Overexpressing 14-3-3, a family of conserved acidic proteins, enhances aggresome formation of several aggregation-prone proteins including alpha-SynEGFP, GFP-250 and GFP-CFTRΔF508, while blocking 14-3-3's binding ability by its antagonist suppresses aggresome formation in cells. In addition, we find that 14-3-3 interacts with both dynein intermediate chain (DIC) and a HSP70 co-chaperone Bcl-2-associated athanogene 3 (BAG3). Our biochemical and functional studies further reveal that dimeric 14-3-3 bindings bridge the interaction between BAG3 and DIC, which is crucial for both loading of misfolded protein cargos onto dynein complex and aggresome formation. Taken together, these findings suggest that 14-3-3 functions as a molecular adaptor by coupling BAG3-cargo-complex with dynein motor for targeting misfolded proteins to aggresome in cells.
A Dissertation submitted to the Department of Biomedical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Includes bibliographical references.
Yi Zhou, Professor Directing Dissertation; Robert Contreras, University Representative; Mohamed Kabbaj, Committee Member; Yanchang Wang, Committee Member.
Florida State University
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