Vidyadhara D J, MSc, PhD

I am a neurobiologist specializing in Parkinson’s disease and neurodegeneration research, with a background in medical physiology. I am interested in studying the role of presynaptic endolysosomal system in neurodegeneration, particularly in Parkinson’s disease, with a long-term goal of unravelling how genetic and environmental perturbations disrupt presynaptic terminals and their aging, leading to neurodegeneration.

My journey so far: For over 12 years, I have been fortunate to work on diverse projects to enhance our understanding of neurodegenerative diseases, especially Parkinson’s disease (PD). My foundation in this field began during my 3-year teaching-intensive Master’s in Medical Physiology, where I gained deep knowledge of how our body functions. This helped me view scientific inquiries through a broad lens, identify translational potential, and prioritize patient-centered impacts; a perspective that has been central to my research. During my Master’s, I also modeled ischemic stroke in rats to develop therapeutics, igniting my passion for the motor system and its disorders. This drove my PhD research in PD, revealing mechanisms behind mice strain-dependent susceptibility to parkinsonian toxin MPTP, shedding light on ethnicity-based differences in PD prevalence. Additionally, we pioneered the delineation of age-related glial changes in the human nigra, which significantly contributed to the morphology-based identification of glial cell activation. Expertise in histopathological, circuit, and behavior abnormalities of PD followed. Collaborations for PD drug development and exposure to patient deep brain stimulation surgeries further solidified my dedication to PD research, a commitment I carried into my postdoc at Yale.

I developed expertise in the genetics and cell biology of PD during my postdoc, with projects centered on endolysosomal dysfunctions. I authored a highly cited review on this topic within a year of joining. I put conscious efforts to parallelly work on two projects, one pioneering and another with established significance. In the first, we unveiled how auxilin-linked PD involves dopamine transporter and synaptic vesicle sorting defects, using auxilin knockout (KO) mice and patient iPSC derived neurons. I am funded by MJFF as co-Principal Investigator to study this further. While establishing the importance of auxilin and its function of presynaptic endocytosis in PD, this study also contributed a novel auxilin KO mice model of PD. We used this model for PD drug development with Dalibor Sames Lab at Columbia University, and to study mechanisms for visual hallucinations in PD with Alexander Chubykin Lab at Purdue University. In the second project where I received DoD Early Career Investigator Award as a Principal Investigator, we delved into mechanisms of cognitive dysfunction in PD and dementia with Lewy bodies. We first showed that GBA-SNCA double mutant mice are a good model to study these conditions, and using snRNA-seq and proteomics, we uncovered synaptic anomalies and a novel putative modifier of GBA-linked PD. Please see my CV for the details on these two projects. I also contributed to studying olfactory dysfunction in PD and neuroinflammation in neuropathic Gaucher disease, and authored a methods article on brain subcellular fractionation.

I've also ardently pursued leadership and teaching opportunities, gaining experience in independently steering projects, fostering collaborations, and mentoring students, all within an inclusive environment. Yale University recognized my undergrad mentorship with an award, while one of my undergrads won Yale Outstanding Student Employee award. I've raised and managed grants, communicated findings through diverse channels, maintained regulatory protocols for the lab, contributed to Yale Neuroscience Dean search and to establishing a high-throughput imaging core. I have been committed to nurturing inclusivity in science by engaging in diverse teaching programs, neuroscience outreach and diversity-enhancing activities, and in my role as a founding member of the Yale Neuroscience Postdoc Committee. I am honored to be chosen as an Associate for the highly competitive Intersection Science Fellow Symposium (ISFS) 2023, which mentors select postdocs for the faculty job market.

My future research: Dopaminergic presynaptic terminals are often the initial sites affected by neurodegeneration in PD. Nevertheless, their remarkable adaptability and dynamic nature within an otherwise post-mitotic soma present a substantial potential for novel PD therapeutics, if we gain an understanding of the factors underlying early presynaptic degeneration. Recent advances in PD genetics and cell biology have spotlighted the putative role played by the presynaptic endolysosomal system in early degeneration, particularly in processes such as presynaptic clathrin-mediated endocytosis and autophagy. My primary objective as a faculty member is to comprehend how dysfunction within the presynaptic endolysosomal system contributes to neurodegenerative mechanisms in PD. I plan to investigate novel PD-related mutations within presynaptic endolysosomal proteins, exploring their interactions with genetic and environmental risk factors, as well as the influence of age. These studies will reveal insights for innovative treatments and biomarker discovery in PD and related neurodegenerative conditions. With my extensive expertise in PD research and specialized training in endolysosomal dysfunctions, I'm well-prepared to take up this exciting and important work.