Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut, USA.
J Neurochem. 2019 Sep;150(5):487-506. doi: 10.1111/jnc.14820. Epub 2019 Jul 31.
Parkinson's disease (PD) is one of the most common neurodegenerative disorders, affecting 1-1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E-L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin-mediated synaptic endocytosis, an integral part of the neuronal E-L system, is probably the main early target as evident in auxilin, RME-8, and synaptojanin-1 mutations that cause PD. Autophagy, another important pathway in the E-L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life-time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi-compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α-synuclein and LRRK2, key proteins involved in PD, function in different steps of the E-L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E-L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue "Synuclein".
帕金森病（PD）是最常见的神经退行性疾病之一，影响总人口的 1-1.5%。虽然在理解导致 PD 晚期细胞死亡的神经退行性机制方面已经取得了进展，但导致早期因果致病事件的机制仍然难以捉摸。PD 遗传学的最新进展越来越多地指出内溶酶体（E-L）系统功能障碍是 PD 的早期病理机制和关键途径。网格蛋白介导的突触内吞作用是神经元 E-L 系统的一个组成部分，可能是主要的早期靶点，正如导致 PD 的辅助蛋白、RME-8 和突触结合蛋白-1 突变所表明的那样。另一个 E-L 系统中的重要途径是自噬，在维持蛋白质平衡和健康的线粒体池中至关重要，特别是在神经元中，因为它们不能分裂，需要整个生命周期的功能。PINK1 和 Parkin 突变严重扰乱了功能失调的线粒体（自噬）的自噬，无论是在多巴胺能神经元的细胞体还是突触末端，导致 PD。内溶酶体分选和运输也很重要，在多室化神经元中很复杂。PD 中注意到的 VPS35 和 VPS13C 突变靶向这些机制。GBA 中的突变构成了 PD 的最常见危险因素，并通过损害溶酶体功能引发病理学。ATP13A2 突变也是如此。有趣的是，α-突触核蛋白和 LRRK2，PD 中涉及的关键蛋白，在 E-L 途径的不同步骤中发挥作用，并靶向它们的成分来诱导疾病发病机制。在这篇综述中，我们讨论了与 PD 相关的这些 E-L 系统基因，以及它们的功能障碍如何导致 PD 发病机制。本文是“突触核蛋白”特刊的一部分。
