Comparative transcription analysis across LRRK2 models of Parkinson's Diesase to identify early pathways in disease pathogenesis (360G-Wellcome-092762_Z_10_A)

The goal of this project is to identify the earliest cellular pathways involved in Parkinson's Disease pathogenesis by examining the effect of the causative G2019S and R1441C LRRK2 mutations on the transcriptome of SNpc dopaminergic neurons. Towards this goal, this project consists of three distinct and complementary aims: 1) To identify and compare the perturbations in cellular pathways caused by G2019S and R1441C mutant LRRK2 in advance of PD pathology in vitro through high-resolution transcriptome analysis of the most physiologically relevant cell culture model of human SNpc dopaminergic neurons currently available. 2) To examine the emergence and evolution of these perturbations in the cell biology of SNpc dopaminergic neurons over the time course of disease progression within a whole organism using a LRRK2 bacterial artificial chromosome transgenic rat model of PD. 3) To assess the physiological and pathophysiological relevance of human induced pluripotent stem cell models to healthy and diseased human SNpc and to examine differential effects of G2019S and R1441C mutations in states of advanced disease through comparison with human post-mortem tissue from LRRK2 mutant carriers and healthy controls.