Nuffield Department of Clinical Neurosciences and Oxford Parkinson's Disease Center, University of Oxford, Oxford, United Kingdom.
Mov Disord. 2012 Sep 15;27(11):1364-9. doi: 10.1002/mds.25136. Epub 2012 Aug 23.
Although the pathogenesis of Parkinson's disease (PD) is considered multifactorial, evidence from genetics and cell biology has implicated specific molecular pathways. This article summarizes evidence that suggests that the level of intracellular alpha-synuclein is critical for the onset of neurodegeneration with Lewy bodies and dependent, to a large extent, on lysosomal degradation. The function of other key proteins that emerged from genetics is discussed: Pink1 and Parkin regulate the degradation of damaged mitochondria by the lysosome (mitophagy). Glucocerebrosidase and ATP13A2 are important components of this degradative organelle. VPS35 and LRRK2 may regulate trafficking within lysosome-dependent pathways, such as autophagy and endosomal vesicle recycling. Clinically, diffuse alpha-synucleinopathy or dementia seems to correlate with mutations which interfere with the broader function of lysosomal pathways, whereas a predominantly motor syndrome and nigrostriatal degeneration is associated with specific defects in mitophagy. Based on these studies, it is proposed that a protein network involved in trafficking to, or degradation by, lysosomes could be sufficient to explain the phenotypic spectrum within PD in a unifying biochemical pathway.
虽然帕金森病 (PD) 的发病机制被认为是多因素的，但遗传学和细胞生物学的证据表明了特定的分子途径。本文总结了表明细胞内α-突触核蛋白水平对于路易体相关性神经退行性变的发生至关重要的证据，并且在很大程度上依赖于溶酶体降解。从遗传学中出现的其他关键蛋白的功能也进行了讨论：Pink1 和 Parkin 调节溶酶体（线粒体自噬）对受损线粒体的降解。葡萄糖脑苷脂酶和 ATP13A2 是这个降解细胞器的重要组成部分。VPS35 和 LRRK2 可能调节溶酶体依赖性途径（如自噬和内体囊泡再循环）中的运输。临床上，弥漫性α-突触核蛋白病或痴呆症似乎与干扰溶酶体途径广泛功能的突变相关，而主要的运动综合征和黑质纹状体变性与线粒体自噬的特定缺陷相关。基于这些研究，提出了一个涉及溶酶体运输或降解的蛋白质网络，可能足以在一个统一的生化途径中解释 PD 中的表型谱。
