Parkinson?s disease (PD) is a common neurodegenerative disease characterized by progressive degeneration of dopaminergic neurons in the midbrain. At present, PD is incurable. A roadblock halting development of effective therapy for PD is the limited understanding of PD pathogenesis. While most PD cases are sporadic without an ascertained cause, about 10% of PD cases are likely caused by mutation of a known or unknown gene. Genetic clues not only help define the molecular pathways leading to neurodegeneration but also help identify biomarkers for monitoring disease progression and therapeutic effectiveness. Compared to the other neurodegenerative diseases, genetic discovery for PD is significantly deferred. One reason for deferred genetic discovery in PD is the incomplete penetrance of disease phenotypes in PD and it is particularly true for late-onset PD. A compelling need for PD research is identifying and validating the genes segregating with late-onset PD. Recently the new gene TMEM230 was reported to cosegregate with disease in a large family affected by late-onset PD. Once after a novel disease gene is identified, enormous efforts are required to validate the authenticity of the pathogenic role of the mutant gene in the disease. First, genetic variants cosegregating with the disease must be verified in independent families afflicted with the disease. Second, disease phenotypes observed in patients carrying the genetic variant must be reproduced in animal models expressing the disease-associated mutation. Third, mechanistic studies must be fulfilled to reveal how the disease-linked mutation impairs cellular functions and thus to determine how these new mechanisms are integrated into existing pathways leading to cell death in the disease. Validating process often takes many years to consolidate the authenticity of a genetic mutation after a disease gene is identified. In the proposed studies, we will take comprehensive approaches to validating the pathogenic role of TMEM230 mutation in late-onset PD by using both cell culture and animal models. Upon completion, our study will determine the effect of TMEM230 mutation on neuronal functions at both systemic and molecular levels.