Neutral lysophosphatidylcholine mediates α-synuclein-induced synaptic vesicle clustering
Ying Lai, Chunyu Zhao, Zhiqi Tian, Chuchu Wang, Jiaqi Fan, Xiao Hu, Jia Tu, Tihui Li, Jeremy Leitz, Richard A. Pfuetzner, Zhengtao Liu, Shengnan Zhang, Zhaoming Su, Jacqueline Burré, Dan Li, Thomas C. Südhof, Zheng‐Jiang Zhu, Cong Liu, Axel T. Brünger, Jiajie Diao
Abstract
α-synuclein (α-Syn) is a presynaptic protein that is involved in Parkinson’s and other neurodegenerative diseases and binds to negatively charged phospholipids. Previously, we reported that α-Syn clusters synthetic proteoliposomes that mimic synaptic vesicles. This vesicle-clustering activity depends on a specific interaction of α-Syn with anionic phospholipids. Here, we report that α-Syn surprisingly also interacts with the neutral phospholipid lysophosphatidylcholine (lysoPC). Even in the absence of anionic lipids, lysoPC facilitates α-Syn-induced vesicle clustering but has no effect on Ca 2+ -triggered fusion in a single vesicle–vesicle fusion assay. The A30P mutant of α-Syn that causes familial Parkinson disease has a reduced affinity to lysoPC and does not induce vesicle clustering. Taken together, the α-Syn–lysoPC interaction may play a role in α-Syn function.