This application is for a K08 Career Development Award for Dr. Rizwan Akhtar, who is an Instructor in Neurology at the University of Pennsylvania (U Penn). The candidate is establishing his career as a neurologist - neuroscientist in the fields of movement disorders and neurodegenerative disease. The objective of this five-year project is to develop two new biomarkers based on alpha-synuclein and apply these biomarkers to the study of Parkinson disease (PD). The candidate is mentored by Drs. Virginia Lee and John Trojanowski, who co-direct the Center for Neurodegenerative Disease Research (CNDR) at U Penn, and by Dr. Matthew Stern, Director of the Parkinson Disease and Movement Disorders Center (PD&MDC) at U Penn. These individuals have a long history of training successful physician - scientists. The CNDR is a multi- disciplinary research laboratory with in-house expertise in protein biochemistry and molecular biology, cell culture, microscopy, histopathology, small animal surgery, drug development, and high throughput assays. The CNDR and PD&MDC also have a multimodal database of clinical data, biological fluid samples, imaging studies, and autopsy specimens cultivated via several NIH funded Program Project Grants at U Penn, which the candidate will utilize to achieve the Aims of this project. The candidate has assembled a team of clinical and research mentors and a structured training plan to develop the necessary skill-set to transition to independence in neurodegenerative disease research. Alpha-synuclein is an amyloid genic protein and thought to be central to the pathogenesis of PD. When misfolded, phosphorylated, or post-transnationally modified, alpha-synuclein appears to confer toxicity to cells by adopting pathological conformations. While all patients with PD have neuron loss and protein aggregates that contain alpha-synuclein in the brain, not all patients follow the same disease course or develop the same complications. The clinical heterogeneity of PD remains poorly explained by what is known regarding the underlying neuropathology. There are currently no biomarkers to measure the spread of alpha-synuclein pathology through the brain, and no treatments for PD appear to modify the disease course. This project will test the hypothesis that alpha-synuclein auto-antibodies (Aim #1) and pathologic forms of alpha-synuclein (Aim #2) are biomarkers for PD. The approach taken will be to develop two ELISA based assays for these biomarkers, and then validate each assay in a mouse model of transmissible synucleinopathy (Aim #3). Each assay will be rigorously tested using newly generated antibodies and truncated, phosphorylated, and fibrillary forms of recombinant alpha-syncline. Once developed, these assays will be used to test serum and CSF from CNDR and correlate each biomarker to clinical disease state using a multi-modal approach. This project will provide the necessary research skills and training to allow the candidate to translate these biomarkers to clinical care and to develop an independent research laboratory focused on mechanisms of PD pathogenesis.