The development of neuroprotective strategies for Parkinson’s disease (PD) is a vital unmet need. As stated in the Report to the NINDS Council (PD2014), “the community of investigators focused on PD now strives to create therapies that meaningfully slow or stop the disease mechanisms that underlie all symptoms of PD”. The Alabama Udall Center is a response to these needs, and a product of our work under an NINDS Exploratory Grant Program in Parkinson's Disease Research (P20NS092530). It has long been recognized that in post-mortem brain tissue from PD there is activation of the innate immune system, with prominent microgliosis in the substantia nigra together with enhanced production of cytokines and chemokines. Recently, it has become clear that there is also activation of adaptive immunity, with infiltration of T-cells and accumulation of immunoglobulins in perineural regions. We envisage that a better understanding of immune changes in PD will identify specific targets and therapeutic strategies that will block neurodegeneration. This Center will address two overall scientific Aims: 1) to determine the extent and nature of immune activation in early human PD; and 2) to determine whether inhibiting LRRK2 and JAK/STAT signaling pathways can block immune responses that underlie alpha-synuclein linked neurodegeneration. Our central hypothesis is that innate and adaptive immune cells, particularly monocytes and T-cells, are activated early in disease, and that blocking LRRK2 or JAK/STAT signaling in these cells will protect from neurodegeneration. We will utilize advanced small molecule ligands and inhibitors, genetic approaches, detailed studies of subsets of immune cells and bone marrow transplantation approaches to test the hypothesis. Each project is anchored through the Clinical Core that will provide samples from human subjects, and the Animal Models Core that harmonizes pre-clinical studies in the alpha-synuclein mouse fibril model of PD. The Alabama Udall Center also has important missions related to training and outreach. We seek to train the next generation of scientists and physicians, to accelerate progress towards PD treatments and cures of the future. We will engage the community of persons with PD who are our partners in these efforts. We seek to create a team and environment focused on the identification of innate and adaptive immune responses critical to PD pathogenesis, and rapidly advance an innovative, interdisciplinary, highly impactful research program.