Proteinaceous inclusions containing alpha-synuclein (α-Syn) have been implicated in neuronal toxicity in Parkinson’s disease, but the pathways that modulate toxicity remain enigmatic. Here, we used a targeted proteomic assay to simultaneously measure 269 pathway activation markers and proteins deregulated by α-Syn expression across a panel of 33 Saccharomyces cerevisiae strains that genetically modulate α-Syn toxicity. Applying multidimensional linear regression analysis to these data predicted Pah1, a phosphatase that catalyzes conversion of phosphatidic acid to diacylglycerol at the endoplasmic reticulum membrane, as an effector of rescue. Follow-up studies demonstrated that inhibition of Pah1 activity ameliorates the toxic effects of α-Syn, indicate that the diacylglycerol branch of lipid metabolism could enhance α-Syn neuronal cytotoxicity, and suggest a link between α-Syn toxicity and the biology of lipid droplets.

含有 α-突触核蛋白 (α-Syn) 的蛋白质内含物与帕金森病的神经元毒性有关，但调节毒性的途径仍然是个谜。在这里，我们使用靶向蛋白质组学测定同时测量了 33 种酿酒酵母菌株中 269 个通路激活标记物和因 α-Syn 表达失调而调节的蛋白质，这些菌株对 α-Syn 毒性进行遗传调节。对这些数据进行多维线性回归分析，预测 Pah1（一种在内质网膜上催化磷脂酸转化为二酰甘油的磷酸酶）作为救援效应器。后续研究表明，抑制 Pah1 活性可改善 α-Syn 的毒性作用，表明脂质代谢的二酰甘油分支可以增强 α-Syn 神经元细胞毒性，并表明 α-Syn 毒性与脂滴生物学之间存在联系。