Sequestration of synaptic proteins by alpha-synuclein aggregates leading to neurotoxicity is inhibited by small peptide

α-Synuclein (α-syn) is a major component of Lewy bodies found in synucleinopathies including Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB). Under the pathological conditions, α-syn tends to generate a diverse form of aggregates showing toxicity to neuronal cells and able to transmit across cells. However, mechanisms by which α-syn aggregates affect cytotoxicity in neurons have not been fully elucidated. Here we report that α-syn aggregates preferentially sequester specific synaptic proteins such as vesicle-associated membrane protein 2 (VAMP2) and synaptosomal-associated protein 25 (SNAP25) through direct binding which is resistant to SDS. The sequestration effect of α-syn aggregates was shown in a cell-free system, cultured primary neurons, and PD mouse model. Furthermore, we identified a specific blocking peptide derived from VAMP2 which partially inhibited the sequestration by α-syn aggregates and contributed to reduced neurotoxicity. These results provide a mechanism of neurotoxicity mediated by α-syn aggregates and suggest that the blocking peptide interfering with the pathological role of α-syn aggregates could be useful for designing a potential therapeutic drug for the treatment of PD.α-突触核蛋白（α-Synuclein, α-syn）是包括帕金森病（Parkinson’s disease, PD）与路易体痴呆（Dementia with Lewy Bodies, DLB）在内的突触核蛋白病（synucleinopathies）患者体内路易体的主要组成成分。在病理条件下，α-syn易形成多种形态的聚集体，这类聚集体对神经元具有毒性，且可在细胞间传播。然而，α-syn聚集体介导神经元细胞毒性的具体机制尚未完全阐明。本研究发现，α-syn聚集体可通过耐十二烷基硫酸钠（SDS）的直接结合作用，优先螯合特定突触蛋白，如囊泡相关膜蛋白2（vesicle-associated membrane protein 2, VAMP2）与突触体相关蛋白25（synaptosomal-associated protein 25, SNAP25）。该螯合效应在无细胞体系、原代培养神经元及PD小鼠模型中均得到验证。此外，我们还鉴定出一种源自VAMP2的特异性封闭肽，该肽可部分抑制α-syn聚集体的螯合作用，并有效减轻神经毒性。本研究结果阐明了α-syn聚集体介导的神经毒性机制，同时提示靶向干扰α-syn聚集体病理作用的封闭肽，有望为帕金森病的潜在治疗药物研发提供新方向。