Classic linkage studies in multigenerational families have identified a number of genes that harbor muta- tions that cause neurodegeneration. The Mayo Clinic Udall Center investigators have successfully driven many of these studies and gene identification is one of the greatest strengths of our Center. Recently, the development of next-generation sequencing technologies has led to a shift in genetic studies, allowing the use of smaller pedigrees for which only a limited number of DNA samples are available and dramatically reducing the time it takes to identify new genes. Our Project sets out to use whole-genome sequencing in our unique collection of families with neurodegeneration to identify novel genes for Parkinsonian a-synucleinopathies (Aim 1) and tauopathies (Aim 2). Families are selected based on the availability of DNA samples from at least 3 affecteds, preferentially including an affected cousin-pair, autopsy confirmation of Lewy-body pathology or tau pathology, and exclusion of mutations in all known autosomal dominant Par- kinson's disease (PD) genes and the microtubule associated protein tau gene, MAPT. Novel variants will be prioritized based on the type of mutation and analyzed in a strictly defined manner. To determine whether rare and common variants in novel causal Parkinsonian genes confer risk to the general population of PD and progressive supranuclear palsy (PSP) patients, in-depth association studies of novel Parkinsonian genes will subsequently be performed (Aim 3). Coding variants identified by candi- date gene sequencing combined with haplotype-tagging variants across the candidate gene loci selected from public databases will be included. Significantiy associated variants will be further studied by assessing their influence on gene and protein expression, and the potential interaction with tau and a-synuclein biolo- gy. The discovery of novel genes and genetic risk factors, as proposed in this Project, will unquestionably contribute to a better understanding of the disease mechanism associated with tau and a-synuclein dys- function in Parkinsonian disorders. Moreover, the identification of novel Parkinsonian genes will further al- low the development of novel etiologic and symptomatic disease models in which new therapies can be evaluated. RELEVANCE (See instructions): This proposal is designed to identify novel causal genes in families with Parkinsonism and a-synuclein or tau pathology using whole-genome sequencing. The proposed studies will contribute to our understanding of and our ability to treat patients with Parkinsonism through improved patient diagnosis, the ability to de- velop novel etiologic disease models and an increased understanding of the disease mechanism associated with tau and a-synuclein dysfunction.