Parkinson's disease (PD) is characterized by dopaminergic neuronal loss and the presence of intra-neuronal Lewy body (LB) inclusions with aggregated α-synuclein (α-Syn) as the major component. MAOB, a crucial monoamine oxidase for dopamine metabolism, triggers oxidative stress in dopaminergic neurons and α-Syn aggregation. However, the key molecular mechanism that mediates PD pathogenesis remains elusive. Here we show that C/EBPβ acts as an age-dependent transcription factor for both α-Syn and MAOB, and initiates the PD pathologies by upregulating these two pivotal players, in addition to escalating δ-secretase activity to cleave α-Syn and promotes its neurotoxicity. Overexpression of C/EBPβ in human wild-type α-Syn transgenic mice facilitates PD pathologies and elicits motor disorders associated with augmentation of δ-secretase, α-Syn, and MAOB. In contrast, depletion of C/EBPβ from human α-Syn Tg mice abolishes rotenone-elicited PD pathologies and motor impairments via downregulating the expression of these key factors. Hence, our study supports that C/EBPβ/δ-secretase signaling mediates PD pathogenesis via regulating the expression and cleavage of α-Syn and MAOB.

中文翻译：

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C /EBPβ/δ-分泌酶信号传导通过调节α-突触核蛋白和MAOB的转录和蛋白水解切割来介导帕金森氏病的发病机理。

帕金森氏病（PD）的特征是多巴胺能神经元缺失和以聚集的α-突触核蛋白（α-Syn）为主要成分的神经内路易体（LB）夹杂物的存在。MAOB是一种对多巴胺代谢至关重要的单胺氧化酶，可触发多巴胺能神经元和α-Syn聚集的氧化应激。然而，介导PD发病机理的关键分子机制仍然难以捉摸。在这里，我们显示C /EBPβ充当α-Syn和MAOB的年龄依赖性转录因子，并通过上调这两个关键参与者来启动PD病理，除了逐步增加δ-分泌酶的活性以切割α-Syn并促进它的神经毒性。在人类野生型α-Syn转基因小鼠中C /EBPβ的过度表达促进了PD病理并引发了与δ-分泌酶，α-Syn，和MAOB。相反，人类α-SynTg小鼠的C /EBPβ耗竭通过下调这些关键因子的表达而消除了鱼藤酮引起的PD病理学和运动障碍。因此，我们的研究支持C /EBPβ/δ-分泌酶信号传导通过调节α-Syn和MAOB的表达和裂解来介导PD的发病机制。