The pathogenesis of Parkinson's disease (PD) remains elusive. There is still no available disease-modifying strategy against PD, whose management is mainly symptomatic. A growing amount of preclinical evidence shows that a complex interplay between autophagy dysregulation, mitochondrial impairment, endoplasmic reticulum stress, oxidative stress, and excessive neuroinflammation underlies PD pathogenesis. Identifying key molecules linking these pathological cellular processes may substantially aid in our deeper understanding of PD pathophysiology and the development of novel effective therapeutic approaches. Emerging preclinical evidence indicates that apelin, an endogenous neuropeptide acting as a ligand of the orphan G protein-coupled receptor APJ, may play a key neuroprotective role in PD pathogenesis, via inhibition of apoptosis and dopaminergic neuronal loss, autophagy enhancement, antioxidant effects, endoplasmic reticulum stress suppression, as well as prevention of synaptic dysregulation in the striatum, excessive neuroinflammation, and glutamate-induced excitotoxicity. Underlying signaling pathways involve phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin, extracellular signal-regulated kinase 1/2, and inositol requiring kinase 1α/XBP1/C/EBP homologous protein. Herein, we discuss the role of apelin/APJ axis and associated molecular mechanisms on the pathogenesis of PD in vitro and in vivo and provide evidence for its challenging therapeutic potential.

中文翻译：

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apelin/APJ 轴在具有治疗潜力的帕金森病发病机制中的影响

帕金森病 (PD) 的发病机制仍然难以捉摸。仍然没有针对 PD 的疾病缓解策略，其管理主要是对症的。越来越多的临床前证据表明，自噬失调、线粒体损伤、内质网应激、氧化应激和过度神经炎症之间的复杂相互作用是 PD 发病机制的基础。识别连接这些病理细胞过程的关键分子可能有助于我们更深入地了解 PD 病理生理学和开发新的有效治疗方法。新出现的临床前证据表明，apelin 是一种内源性神经肽，作为​​孤儿 G 蛋白偶联受体 APJ 的配体，可能在 PD 发病机制中发挥关键的神经保护作用，通过抑制细胞凋亡和多巴胺能神经元丢失、自噬增强、抗氧化作用、内质网应激抑制以及预防纹状体中的突触失调、过度神经炎症和谷氨酸诱导的兴奋性毒性。潜在的信号通路涉及磷酸肌醇 3-激酶 (PI3K)/Akt/雷帕霉素的哺乳动物靶点、细胞外信号调节激酶 1/2 和需要激酶 1α/XBP1/C/EBP 同源蛋白的肌醇。在此，我们讨论了apelin/APJ轴在PD发病机制中的作用及相关分子机制。潜在的信号通路涉及磷酸肌醇 3-激酶 (PI3K)/Akt/雷帕霉素的哺乳动物靶点、细胞外信号调节激酶 1/2 和需要激酶 1α/XBP1/C/EBP 同源蛋白的肌醇。在此，我们讨论了apelin/APJ轴在PD发病机制中的作用及相关分子机制。潜在的信号通路涉及磷酸肌醇 3-激酶 (PI3K)/Akt/雷帕霉素的哺乳动物靶点、细胞外信号调节激酶 1/2 和需要激酶 1α/XBP1/C/EBP 同源蛋白的肌醇。在此，我们讨论了apelin/APJ轴在PD发病机制中的作用及相关分子机制。在体外和体内，并为其具有挑战性的治疗潜力提供证据。