主讲人简介：李丹，现任上海交大Bio-X中心教授、讲师。主要研究方向为电工理论与新技术。
内容摘要：Abnormal α-synuclein (α-syn) aggregation in Lewy bodies is the pathological hallmark of Parkinson’s disease (PD) and other synucleinopathies such as infantile neuroaxonal dystrophy (INAD), and idiopathic neurodegeneration associated with brain iron accumulation (NBIA)1. Despite its high propensity to aggregate under pathological conditions and when isolated in vitro, native α-syn is a highly abundant soluble neuronal protein in the CNS (~1% of the total proteins) and resists aggregation in normal intracellular environments2. However, little is known how α-syn maintains its native structure. Here we systemically investigated lipid-binding partners of α-syn using untargeted global lipidomic profiling. We found that different α-syn species (e.g. monomer, oligomer and fibril) have distinct binding preferences to lipid molecules. We identified a class of lipid molecules which specifically bind with the N-terminal of α-syn monomer, induce a compact α-helical conformation and stabilize α-syn monomer from aggregation. Importantly, this lipid mediates physiological function of α-syn in synaptic vesicle trafficking. PD familial A30P α-syn mutant shows reduced binding affinity with the lipids. Furthermore, decreased production of this class of lipids dramatically promotes α-syn aggregation in cells. Our study suggests that dysfunctions in the lipid homeostasis might be critical in the development of Lewy body diseases.
