Project III: SUMMARY Increasing evidence indicates that neurodegenerative diseases may share overlapping proteinopathies and common molecular mechanisms. The overall goal of this project is to enhance our understanding of the role of two proteins in Parkinson’s Disease (PD). PD is the second most common neurodegenerative disease in the United States and is characterized by the loss of dopaminergic neurons of the substantia nigra. Although most PD cases are idiopathic, genetic causes have been identified including mutations and copy number variants of the gene that encodes alpha synuclein (SNCA) protein, a major component of Lewy body aggregates observed in postmortem PD brain tissue. SNCA has been shown to possess prion properties in that it can induce misfolding and aggregation that can spread from cell to cell. Much less is known about other proteins that may modulate SNCA aggregation and have an impact on PD pathology. This project addresses the hypothesis that Superoxide Dismutase 1 (SOD1) aggregates are correlated with SNCA aggregates in idiopathic PD brain and that they exacerbate disease progression in concert with misfolded SNCA. SOD1 is a major cytoplasmic antioxidant enzyme that metabolizes superoxide radicals; mutations in the SOD1 gene were the first mutations linked to the neurodegenerative disorder Amyotrophic Lateral Sclerosis (ALS). Although several reports indicate SOD1 aggregates occur in postmortem PD brain tissue, the role of SOD1 in PD is not clear. This project builds on substantial preliminary data that demonstrates development of a SOD1 aggregation assay that can detect and propagate misfolded SOD1 in postmortem human neural tissues with high specificity and sensitivity. To address the hypothesis, two aims are proposed: Specific Aim 1 is focused on the use of human tissues and cells to examine the propagation and toxicity of SOD1 aggregates, whereas Specific Aim 2 uses mouse models to test the hypothesis. We will quantify SNCA and SOD1 aggregates in postmortem idiopathic PD brain regions, examine neurotoxicity from idiopathic PD-SOD1 on dopaminergic neurons, and determine whether the presence of the human SOD1 wild type allele exacerbates neurobehavioral deficits and protein aggregation in a PD mouse model expressing human SNCA. This project is significant as it addresses the underlying molecular pathology of a common neurodegenerative disease; the project is also significant in that PD has an outsized impact in rural communities, where incidence of PD has been reported to be higher and access to specialists is limited relative to urban areas. Several aspects of the project are innovative including: 1) the hypothesis, based on shared proteinopathy of SNCA and SOD1, 2) the use of novel tools such as the first SOD1 real time quaking induced conversion (RT-QuIC) assay, and 3) the use of complementary but independent studies in humans and mouse models. Outcomes of this study will shed light on the role of SOD1 in idiopathic PD...