The accumulation of α-synuclein (α-syn), a key protein in Parkinson's disease (PD), contributes to progressive neuronal damage associated with mitochondrial dysfunction and interactions with various proteins. However, the precise mechanism by which α-syn affects energy metabolism remains unclear. In our study, we used human α-syn (hα-syn) transgenic mice, which exhibit progressive neuronal decline. Through an immunoprecipitation assay specific to hα-syn, we identified an enzyme in the mitochondrial tricarboxylic acid (TCA) cycle as a binding partner—mitochondrial aconitase 2 (ACO2), which converts citrate to isocitrate. Hα-syn increasingly interacted with ACO2 in mitochondria as mice aged, correlating with a progressive decrease in ACO2 activity. The overexpression of ACO2 and the addition of isocitrate, a downstream metabolite of ACO2, were observed to alleviate hα-syn-induced mitochondrial dysfunction and cytotoxicity. Furthermore, we designed an interfering peptide to block the interaction between ACO2 and hα-syn, which showed therapeutic effects in reducing hα-syn toxicity in vitro and in vivo. Our research establishes a direct link between α-syn and the TCA cycle and identifies ACO2 as a promising therapeutic target for improving mitochondrial function and reducing α-syn neurotoxicity in PD.

中文翻译：

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α-突触核蛋白与 ACO2 的结合促进帕金森病模型中进行性线粒体功能障碍


α-突触核蛋白 （α-syn） 是帕金森病 （PD） 中的一种关键蛋白，其积累会导致与线粒体功能障碍相关的进行性神经元损伤以及与各种蛋白质的相互作用。然而，α-syn 影响能量代谢的确切机制仍不清楚。在我们的研究中，我们使用了人类 α-syn （hα-syn） 转基因小鼠，它们表现出进行性神经元衰退。通过对 hα-syn 特有的免疫沉淀测定，我们鉴定了线粒体三羧酸 （TCA） 循环中的一种酶作为结合伴侣——线粒体乌头酸酶 2 （ACO2），它将柠檬酸盐转化为异柠檬酸盐。随着小鼠年龄的增长，Hα-syn 越来越多地与线粒体中的 ACO2 相互作用，与 ACO2 活性的逐渐降低相关。观察到 ACO2 的过表达和异柠檬酸盐（ACO2 的下游代谢产物）的添加可减轻 hα-syn 诱导的线粒体功能障碍和细胞毒性。此外，我们设计了一种干扰肽来阻断 ACO2 和 hα-syn 之间的相互作用，在体外和体内显示出降低 hα-syn 毒性的治疗效果。我们的研究建立了 α-syn 和 TCA 循环之间的直接联系，并确定 ACO2 是改善线粒体功能和降低 PD 中 α-syn 神经毒性的有前途的治疗靶点。