Bharat, V.; Durairaj, A. S.; Vanhauwaert, R.; Li, L.; Muir, C. M.; Chandra, S.; Kwak, C. S.; Le Guen, Y.; Nandakishore, P.; Hsieh, C.-H.; Rensi, S. E.; Altman, R.; Greicius, M. D.; Feng, L.; Wang, X.

Genetic backgrounds and risk factors among individuals with Parkinsons disease (PD) are highly heterogenous, limiting our ability to effectively detect and treat PD. Discovering a common pathway connecting several PD risk factors may be crucial for finding a cure. Here we present one such pathway. Elevation of iron levels causes inward mitochondrial Ca2+ overflow, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU). Enhanced Ca2+ influx across the mitochondrial surface causes spatially confined Ca2+ elevation at the outer mitochondrial membrane (OMM), which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover FDA-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology, and drug targets and candidates coupled with a convenient stratification method.