That certain cell types in the central nervous system are more likely to undergo neurodegeneration in Parkinson's disease is a widely appreciated but poorly understood phenomenon. Many vulnerable subpopulations, including dopamine neurons in the substantia nigra pars compacta, have a shared phenotype of large, widely distributed axonal networks, dense synaptic connections, and high basal levels of neural activity. These features come at substantial bioenergetic cost, suggesting that these neurons experience a high degree of mitochondrial stress. In such a context, mechanisms of mitochondrial quality control play an especially important role in maintaining neuronal survival. In this review, we focus on understanding the unique challenges faced by the mitochondria in neurons vulnerable to neurodegeneration in Parkinson's and summarize evidence that mitochondrial dysfunction contributes to disease pathogenesis and to cell death in these subpopulations. We then review mechanisms of mitochondrial quality control mediated by activation of PINK1 and Parkin, two genes that carry mutations associated with autosomal recessive Parkinson's disease. We conclude by pinpointing critical gaps in our knowledge of PINK1 and Parkin function, and propose that understanding the connection between the mechanisms of sporadic Parkinson's and defects in mitochondrial quality control will lead us to greater insights into the question of selective vulnerability.

中文翻译：

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PINK1 和 Parkin 线粒体质量控制：帕金森病区域脆弱性的来源。

中枢神经系统中的某些细胞类型更有可能在帕金森病中发生神经变性，这是一种广泛认识但知之甚少的现象。许多脆弱的亚群，包括黑质致密部的多巴胺神经元，具有共同的表型：大而广泛分布的轴突网络、密集的突触连接和高基础神经活动水平。这些特征是以巨大的生物能量成本为代价的，这表明这些神经元经历了高度的线粒体应激。在这种情况下，线粒体质量控制机制在维持神经元存活方面发挥着特别重要的作用。在这篇综述中，我们重点了解帕金森病中易受神经变性影响的神经元中线粒体面临的独特挑战，并总结了线粒体功能障碍导致这些亚群的疾病发病机制和细胞死亡的证据。然后，我们回顾了由 PINK1 和 Parkin 激活介导的线粒体质量控制机制，这两个基因携带与常染色体隐性遗传帕金森病相关的突变。最后，我们指出了我们对 PINK1 和 Parkin 功能的了解中的关键差距，并提出，了解散发性帕金森病的机制与线粒体质量控制缺陷之间的联系将使我们对选择性脆弱性问题有更深入的了解。