The main pathological hallmark of Parkinson's disease (PD) is the presence of Lewy bodies, which mainly consist of aggregated α-synuclein. Based on the neurotoxicity of oligomeric α-synuclein and its significance in the aetiology of PD, there has been decades of effort to elucidate an enzyme specifically degrading oligomeric α-synuclein. Here we report an enzyme, Omi, which specifically recognizes and precisely degrades oligomeric α-synuclein but not monomeric α-synuclein. After enzymatic and functional analyses of Omi in in vitro, we developed an in vivo assay system of dual gene interaction in Drosophila to investigate further the etiological role of Omi in PD. Pan-neuronal expression of Omi rescued Parkinsonism in a Drosophila model of PD, while Knockout of Omi exacerbated Parkinsonism. Expression of Omi counteracted the α-synuclein-induced retinal degeneration, providing additional evidence for Omi's protective role oligomeric α-synuclein. This work reports identification of the catabolic pathway of oligomeric α-synuclein as well as showing how Omi functions as the key molecule in the recognition and degradation of toxic oligomeric α-synuclein, a possible cause of neurodegeneration in PD, without affecting monomeric α-synuclein which is a native essential molecule for the normal function of neurons.

中文翻译：

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Omi对α-突触核蛋白诱导的神经毒性的神经保护作用。

帕金森氏病（PD）的主要病理特征是路易体的存在，主要由聚集的α-突触核蛋白组成。基于寡聚α-突触核蛋白的神经毒性及其在PD病因中的意义，已经进行了数十年的努力来阐明特异性降解寡聚α-突触核蛋白的酶。在这里，我们报告了一种酶Omi，该酶可特异性识别并精确降解寡聚α-突触核蛋白，但不能降解单体α-突触核蛋白。在对Omi进行体外酶和功能分析后，我们开发了一种在果蝇中双基因相互作用的体内测定系统，以进一步研究Omi在PD中的病原学作用。Omi的泛神经表达在PD的果蝇模型中挽救了帕金森病，而Omi的敲除加剧了帕金森病。Omi的表达抵消了α-突触核蛋白诱导的视网膜变性，为Omi的寡聚α-突触核蛋白的保护作用提供了额外的证据。这项工作报告了寡聚α-突触核蛋白的分解代谢途径的鉴定，并展示了Omi如何作为识别和降解有毒寡聚α-突触核蛋白（PD中神经变性的可能原因，而不会影响单体α-突触核蛋白）的关键分子。这是神经元正常功能的天然必需分子。