Role of 14-3-3θ in Environmental Toxicant Exposure and Neuroinflammation in Synucleinopathies

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Project Summary The purpose of this NIH F31 application is to obtain support for the PI, W. Jay Stone, for mentored research and career development activities within his MD/PhD degree training that will strengthen his potential to become a successful physician scientist. The project goal is to develop skills in neuroscience that will allow the PI to study key proteins involved in the pathogenesis of synucleinopathies, including Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB), using laboratory assays foundational to research in neuroscience. The primary objective of this research proposal is to investigate the role of 14-3-3θ phosphorylation in the context of environmental toxicant exposure and the neuroinflammatory response associated with synucleinopathies. Work from the lab of Dr. Talene Yacoubian, sponsor of the PI, has established 14-3-3θ as a key mediator of pathologic mechanisms by which neurons degenerate in models of PD and DLB, and serves as a potential target for disease modifying therapy. Furthermore, our lab has revealed that phosphorylation of 14-3-3θ at serine residue 232 (pS232) modulates its ability to interact with and prevent the aggregation of α-syn, the critical pathologic protein implicated in PD and DLB. However, the events which lead to aberrant pS232 levels are unclear. This project aims to increase our understanding of the mechanisms that induce pS232 and promote neurodegeneration in two synucleinopathy-associated events: exposure to the environmental toxicant, trichloroethylene (Aim 1) and neuroinflammation (Aim 2). The long-term objective of our research is to better understand the role of 14-3-3θ phosphorylation within synucleinopathies so that subsequent studies can be devised to target 14-3-3θ for developing potential disease-modifying therapeutics. The proposed training plan for Jay Stone is sponsored by his project mentor, Dr. Talene Yacoubian, and co- sponsored by Dr. David Standaert. The overall goal of the training plan is to provide the PI with a solid foundation for a successful career as a physician scientist. A project based both in translational approaches, while focused on a disease-oriented pathogenesis, is the ideal training environment for any aspiring physician scientist. Included in the training plan are experiences that will help Jay develop in three major areas: 1) rigorous neuroscience research in synucleinopathies, which includes developing familiarity with the existing literature, critical evaluation of data, and training in the responsible conduct of research; 2) training in advanced gene therapeutics, and 3) career and professional development, including grant and manuscript writing, scientific communications, and the translation of research findings to clinical applications. This proposal drives the development of skills required to conduct rigorous scientific research in synucleinopathies and advanced neuroscience skills necessary for the PI’s future career as a neurology physician-scientist focused on precision medicine and neurodegenerative diseases.