This application proposes to identify molecular etiologies of heritable movement disorders and elucidate effects of pathogenic variants as important steps towards improving diagnoses and development of targeted therapies. The categories of disease studied in this project, including Parkinson’s disease (PD) and related syndromes, ataxias, spastic paraplegias, and choreiform or dystonic disorders, are all genetically heterogeneous. We have identified the underlying genes for multiple movement disorders, some of which are a focus in this proposal, and initiated studies on their pathogeneses. Many more contributing genes remain to be discovered. We propose to 1) continue to ascertain and characterize individuals and families with genetically unattributed movement disorders; 2) use state-of-art gene mapping and next-generation sequencing technologies to discover new genes for movement disorders; and 3) investigate pathogenic mechanisms of variants using patient tissues, patient-derived stem cell models, and Drosophila models. The proposal builds on established synergistic collaborations and multifaceted clinical, pathological, basic science, and translational expertise of the Investigators and Collaborators. It also leverages the invaluable resources of two large collections of samples ascertained, extensively characterized, and extended over 30 years (Neurogenetics and PD repositories). Our approach to disease gene identification combines traditional linkage or identity-by-descent (IBD) analysis to identify genomic regions shared by all affected family members, together with exome or genome sequencing and copy number variation (CNV) analysis to identify variants in the linkage/IBD region shared by affected relatives. Advances in statistical genetics and use of denser marker panels make it possible to perform such studies in smaller families and more powerful bioinformatics tools offer a stepwise filtering approach to prioritize likely pathogenic variants for further study. Cosegregation of a variant with disease in single families and identification of mutations in the same gene in other families and large publicly available datasets of sporadic cases with the same disorder provide validation that the gene is responsible for the disease. Disease pathogenesis can then be investigated through mechanistic studies. This approach has led to our documented record of consistent productivity in parsing genetic neurologic disorders. For functional studies, we focus on the RAB39B α-synucleinopathy, the ATP6AP2 tauopathy, and SAMD9L ataxia, pancytopenia and autoimmunity syndrome, three disorders whose causative genes we discovered, and GBA, which is the strongest known genetic risk factor for idiopathic PD. These four genes participate in endolysosomal trafficking and autophagy, pathways frequently implicated in PD and other neurodegenerative disorders. By analysis of gene expression in human autopsy brain samples, we will identify vulnerable cell types and c...