Abstract：
Parkinson\'s disease (PD) is a neurodegenerative disorder characterized by progressive dysfunction and loss of dopaminergic neurons of the substantia nigra pars compacta (SNc). Several pathways of programmed cell death are likely to play a role in dopaminergic neuron death, such as apoptosis, necrosis, pyroptosis and ferroptosis, as well as cell death associated with proteasomal and mitochondrial dysfunction. A better understanding of the molecular mechanisms underlying dopaminergic neuron death could inform the design of drugs that promote neuron survival. Necroptosis is a recently characterized regulated cell death mechanism that exhibits morphological features common to both apoptosis and necrosis. It requires activation of an intracellular pathway involving receptor-interacting protein 1 kinase (RIP1 kinase, RIPK1), receptor-interacting protein 3 kinase (RIP3 kinase, RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL). The potential involvement of this programmed cell death pathway in the pathogenesis of PD has been studied by analysing biomarkers for necroptosis, such as the levels and oligomerization of phosphorylated RIPK3 (pRIPK3) and phosphorylated MLKL (pMLKL), in several PD preclinical models and in PD human tissue. Although there is evidence that other types of cell death also have a role in DA neuron death, most studies support the hypothesis that this cell death mechanism is activated in PD tissues. Drugs that prevent or reduce necroptosis may provide neuroprotection for PD. In this review, we summarize the findings from these studies. We also discuss how manipulating necroptosis might open a novel therapeutic approach to reduce neuronal degeneration in PD.
摘要：
帕金森病（PD）是一种神经退行性疾病，其特征是黑质致密质（SNc）的进行性功能障碍和多巴胺能神经元丢失。程序性细胞死亡的几种途径可能在多巴胺能神经元死亡中起作用，如细胞凋亡，坏死,焦凋亡和铁凋亡，以及与蛋白酶体和线粒体功能障碍相关的细胞死亡。更好地了解多巴胺能神经元死亡的分子机制可以为设计促进神经元存活的药物提供信息。坏死性凋亡是最近表征的调节的细胞死亡机制，表现出凋亡和坏死共同的形态学特征。它需要激活涉及受体相互作用蛋白1激酶（RIP1激酶，RIPK1),受体相互作用蛋白3激酶（RIP3激酶，RIPK3）和混合谱系激酶结构域样假激酶（MLKL）。这种程序性细胞死亡途径在PD发病机制中的潜在参与已经通过分析坏死的生物标志物进行了研究。例如磷酸化RIPK3（pRIPK3）和磷酸化MLKL（pMLKL）的水平和寡聚化，在几个PD临床前模型和PD人体组织中。尽管有证据表明其他类型的细胞死亡也在DA神经元死亡中起作用，大多数研究支持这种细胞死亡机制在PD组织中被激活的假设。预防或减少坏死的药物可以为PD提供神经保护。在这次审查中,我们总结了这些研究的发现。我们还讨论了如何操纵坏死可能打开一种新的治疗方法，以减少PD中的神经元变性。
