Jacqueline Burré, PhD Jacqueline Burré, PhD Name of Institution: Joan & Sanford I. Weill Medical College of Cornell University Project Title: Aging increases the aggregation-prone cytosolic pool of alpha synuclein Investigator: Jacqueline Burré, PhD Dr. Burré obtained her PhD in biochemistry from Goethe University in Germany, where she built a comprehensive molecular map of synaptic vesicles. She then trained with Tom Südhof as a postdoctoral fellow, first at UT Southwestern Medical Center in Dallas, and later at Stanford University, where she studied the function and dysfunction of alpha synuclein at the neuronal synapse. She joined Weill Cornell Medical College in February 2014 as Assistant Professor of Neuroscience, where she is continuing her studies of the synuclein protein family and their link to Parkinson’s disease and related synucleinopathies. Research Objectives and Relevance to Diagnosis/Treatment of PD: There is a critical need to understand how aging affects the balance of intracellular alpha synuclein pools, in order to understand sporadic Parkinson’s Disease pathogenesis. The objective of this project is to determine how aging affects the subcellular distribution of alpha synuclein. At the completion of these studies, the hope is to have identified that age-triggered changes in alpha synuclein and membranes increase the aggregation-prone cytosolic pool of alpha synuclein. Successful completion of these studies would be expected to have an important positive impact in understanding sporadic Parkinson’s disease pathogenesis, which may enable the development of therapeutics to slow down or halt the disease process. 2016 Progress Update: In nerve cells, alpha synuclein exists in two states: a lipid-bound state on synaptic vesicles which mediates its normal function in the brain, and a soluble state which we had previously found to trigger pathology in PD. We hypothesized that aging, the biggest risk factor for PD, results in an increase in the soluble state, which subsequently triggers alpha synuclein aggregation and neuropathology. We tested our hypothesis using studies with purified alpha synuclein, studies in cellular systems, and studies in mouse brains. First, in two different alpha synuclein mouse models we found that the soluble state increases with aging. Second, we confirmed these findings in a cell line expressing increasing amounts of alpha synuclein. Third, we found that four out of the six known Parkinson’s Disease mutations in alpha synuclein results in an increase in soluble alpha synuclein. Forth, we discovered that changes in lipids normally occurring during aging trigger an increase in the soluble state of alpha synuclein. Together, our data suggest that aging as well as most Parkinson’s Disease mutations in alpha synuclein cause an increase in the aggregation-prone soluble state of alpha synuclein. We are currently analyzing possible reasons for this increase in the soluble state of alpha synuclein, including changes in alpha synuclein itself and in its environment.