Role of Rab27 Isoforms on Alpha-Synuclein Endocytosis and Clearance - Synucleinopathies, including Parkinson’s Disease (PD) and Lewy Body Dementias such as Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD), are a devastating group of neurodegenerative disorders that cause extensive social and economic burdens worldwide. The prevalence of these diseases is predicted to increase drastically, yet no therapies currently prevent neurodegeneration in PD, PDD, or DLB. Alpha-synuclein (asyn) is the key pathogenic protein that misfolds, aggregates, and induces pathology in PD, PDD, and DLB. Pathogenic asyn spreads from cell to cell throughout the brain, and misfolded asyn species are hypothesized to facilitate the spread of pathology by inducing the misfolding of nonpathogenic species. However, little is known about the exact processes that promote asyn propagation in PD, PDD, and DLB. The goal of this project is to allow the PI (Kacie Scholz) to develop the necessary skills in neuroscience research to study key proteins involved in asyn pathology. The primary objective of this proposal is to investigate the roles of Rab27a and Rab27b on the endocytosis and autophagic-lysosomal degradation of asyn. Previous work from the lab of Dr. Talene Yacoubian, the PI’s sponsor, has identified that Rab27b is upregulated in temporal cortical lysates from human PD and DLB subjects relative to age-matched controls, and that it acts as a mediator of asyn clearance and toxicity in asyn models. Further, our lab has identified Rab27a as a potential mediator of asyn uptake. Both endocytosis and autophagic-lysosomal clearance are critical components of the spread of asyn and asyn-related pathology. In Aim 1, the PI will examine the role of Rab27b in promoting the lysosomal clearance of asyn using in vitro and in vivo asyn models. In Aim 2, she will examine the impact of Rab27a in mediating asyn endocytosis in in vitro and in vivo asyn models. The long-term goals are to advance our understanding of asyn pathology and to identify new therapeutic targets for potential disease-modifying therapies for PD, PDD, and DLB. The proposed training plan for Kacie is sponsored by her project sponsor, Dr. Talene Yacoubian. The overall goal is to provide her with a solid foundation for a successful career in academic science. The training plan includes experiences that will help Kacie develop skills in rigorous neuroscience research in synucleinopathies including training in the responsible conduct of research, critical research techniques, data analysis, and the available literature. It will also expose her to invaluable career and professional development opportunities in areas including scientific communication, translational research skills, and grant and manuscript writing. This proposal will drive the development of the skills needed to conduct rigorous scientific research in synuclein disorders and provide an invaluable foundation for the PI’s future career as an academic scientist focused on neurodegenerative diseases, such as PD, PDD, and DLB.
