Maja Malbasic, “Investigating if RabGTPases the Key Mediators of Pathogenic LRRK-2”
Mentor: An Phu Tran, Biological Sciences
Poster #122

Parkinson’s disease (PD) has been a significant global concern for decades. While the exact cause of PD remains unclear, it is widely believed to result from a combination of genetic and environmental factors. Mutations in various genes have been linked to PD, with mutations in the LRRK2 gene, which encodes leucine-rich repeat kinase 2 (LRRK2), being the most common. LRRK2 is a large, multidomain protein with two distinct and functional enzymatic domains: a Roc-COR GTPase domain and a kinase domain. Familial mutations in LRRK2 typically occur within the kinase domain (e.g., G2019S) or the Roc-COR GTPase domain (e.g., R1441C, Y1699C), commonly leading to enhanced kinase activity and neuronal damage in culture and animal models. The precise mechanism by which pathogenic LRRK2 mutations cause neuronal damage remains poorly understood. While several substrates for LRRK2 kinase activity have been identified, including a subset of Rab-GTPases, it has not been conclusively established whether Rab-GTPases are required for pathogenic LRRK2-mediated neurodegenerative phenotypes. Here we aim to determine whether Rab depletion can attenuate pathogenic LRRK2-induced neurotoxicity. In this study, we have successfully established culture conditions for N27-A rat dopaminergic cells. This cell line is now prepared to be utilized in future research to validate shRNA constructs targeting endogenous Rabs (shRNA-RAB) through transient transfection.