Abnormal accumulation of the protein alpha-synuclein is a pathological hallmark of Parkinson’s disease (PD). We and others have evidence that aggregated alpha-synuclein could harm cells by disrupting the integrity of biological membranes. It remains puzzling, though, how alpha-synuclein is maintained on membranes while performing its normal function. Understanding the lipid and protein factors stabilizing alpha-synuclein could provide new therapeutic avenues and drug targets to combat PD.
Based on our preliminary data, we hypothesize that a class of lipid molecules termed lysophospholipids (lysoPLs) and a protein called VAMP2 (vesicle-associated membrane protein 2) cooperate to stabilize alpha-synuclein on the synaptic vesicle membrane. This, in turn, contributes to proper synaptic vesicle function.
We propose two specific aims to address our hypothesis: (1) Determine the molecular mechanism for lysoPLs- and VAMP2-regulated alpha-synuclein clumping in solution and membrane association; (2) Determine the roles of lysoPLs on alpha-synuclein’s function in membrane fusion. To accomplish these aims, we will use cell-free preparations and multiple biophysical, biochemical and molecular assays, including single-vesicle fusion. Our single-vesicle fusion assays are ideal tools to reveal the physiological function of various alpha-synuclein species on synaptic transmission.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
In solution, alpha-synuclein has a propensity to aggregate to form fibrils that are believed to be toxic to cells and responsible for neurodegeneration. The proposed studies are designed to learn more about the structure, pathways and function of both normal and modified (pathological) forms of alpha-synuclein. Ultimately, these studies will expand the range of alpha-synuclein-related therapeutic avenues for treatment of PD.
Next Steps for Development:
Based on our biochemical and cellular results, our next steps will be to conduct related experiments using a leading PD model, as a prelude to therapeutic drug development.