Alpha-synuclein biomarkers in Parkinson disease

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 amyloidogenic protein and thought to be central to the pathogenesis of PD. When misfolded, phosphorylated, or post-translationally 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