Research & Publications
Research interests: Parkinson's disease, synaptic endocytic dysfunctions in Parkinson's disease, auxilin and GBA mutations in Parkinson's disease.
- Role of clathrin-mediated endocytosis and auxilin in pathogenesis of Parkinson’s disease: Clathrin-mediated endocytosis (CME) is crucial for synaptic vesicle (SV) recycling at the striatal dopaminergic terminals, which degenerate early in Parkinson’s disease (PD). Auxilin, a clathrin uncoating protein plays central role in presynaptic CME, whose loss-of-function mutations cause early-onset PD (PARK19). We used auxilin knockout (KO) mice to elucidate the mechanisms through which auxilin mutations and CME defects lead to PD. Behavior evaluation revealed PD-like progressive motor deficits in auxilin KO mice. This is accompanied by synucleinopathy, decline in striatal dopamine, loss of nigral dopaminergic neurons, and neuroinflammation. Dopaminergic terminals show accumulation of clathrin-coated vesicles suggesting defective CME. At presymptomatic phase, a significant increase in dopamine metabolite DOPAC is seen in the dorsal striatum of auxilin KO mice, suggesting toxic dopamine accumulation. We also noted abnormal dopamine reuptake and misrouting of dopamine transporters. Proteomic analysis also revealed dopamine dysregulation along with SV sorting defects. These observation suggest that the loss of auxilin & CME dysfunction leads to defective striatal dopamine compartmentalization, initiating PD pathogenesis. We are further evaluating these mechanisms using PARK19 patient derived and CRISPR generated auxlin KO iPSCs.
- Role of Lipid Dyshomeostasis in Cognitive Dysfunction of Parkinson's Disease: A large proportion of PD patients suffer from cognitive dysfunction, though the mechanisms are still elusive. Lipid dyshomeostasis has been implicated in a growing number of cognitive disorders, envisaging its contribution to cognitive dysfunction associated with PD. Mutations in GBA gene that encodes glucocerebrosidase 1 leading to accumulation of glycosphingolipids, is the most common genetic risk factor for PD. Cognitive dysfunction is more prevalent and severe in PD patients with GBA mutations. We are using well-established mice models of Gba mutations with PD phenotypes to decipher the role of lipid dyshomeostasis in cognitive dysfunction of PD.
Born in: India
Hobbies: Trekking, biking
Education & Training
- PhDNational Institute of Mental Health and Neurosciences (NIMHANS), Neurophysiology, Parkinson's disease (2018)
- MScKasturba Medical College, Manipal Academy of Higher Education, Medical Physiology (2011)
- BScYuvaraja College, University of Mysore, Biochemistry, Biotechnology & Microbiology (2007)