Research Projects

Protein aggregation is a common feature of many brain diseases. While protein aggregation is often linked to neurodegeneration and memory loss, some proteins form functional aggregates that help in many physiologically vital processes, for example, maintaining long-term memory. In such cases, aggregation is helpful instead of being harmful. However, there is a significant gap in the mechanistic and structural understanding of functional amyloid formation. Also, how functional amyloids of certain proteins maintain memory is unclear. This research proposal aims to address several key questions in the field of functional amyloidosis: Can we counterbalance the harmful effects of disease-causing aggregation by enhancing functional amyloids? Are the aggregation mechanisms in functional and disease-causing amyloids the same or different? What is the aggregation mechanism of functional amyloids? Does the formation of functional amyloids involve multiple intermediates? What factors influence the formation and stability of functional amyloids? How does the mechanism of functional amyloid formation differ from disease-causing aggregation? How do functional amyloids and disease-causing amyloids coexist within the same cellular environment? This research will offer a fresh perspective on functional amyloids and their role in memory maintenance. It may help guide new therapeutic strategies for neurodegenerative disorders. This project will use Cytoplasmic Polyadenylation Element Binding Protein 3 (CPEB3), a neuronal RNA-binding protein, as a model system. CPEB3 is observed to support long-term memory by changing its structure into a stable amyloid form. This study aims to examine the molecular steps and structural features involved during the functional aggregation of CPEB3. The project has four main objectives. First, to develop a method to purify full-length, native CPEB3 in vitro with minimal protein modifications. Second, to study the aggregation mechanism of CPEB3 using biophysical techniques and principles of kinetics and thermodynamics. Third, to analyze the structure and flexibility of the amyloid core of CPEB3 aggregates using hydrogen-deuterium exchange mass spectrometry and binding assays. Fourth, to identify molecules or conditions that help stabilize the functional amyloid form of CPEB3. Harmful protein aggregation is a major cause of neurodegeneration. Treatments like transthyretin inhibitors have helped, but are not enough. Proteins naturally self-assemble, so blocking aggregation is challenging. This work focuses on proteins like CPEB3 that undergo functional amyloid formation and support vital cellular roles. By understanding the mechanism and kinetics of functional amyloid formation, we can better distinguish functional amyloids from harmful aggregates. This work aims to understand the crucial steps in functional amyloids to help plan strategies for treating neurodegeneration.