Schapira Anthony H V
Institute of Neurology, University College London, London, United Kingdom.
Mt Sinai J Med. 2011 Nov-Dec;78(6):872-81. doi: 10.1002/msj.20303.
The last 25 years have witnessed remarkable advances in our understanding of the etiology and pathogenesis of Parkinson's disease. The ability to undertake detailed biochemical analyses of the Parkinson's disease postmortem brain enabled the identification of defects of mitochondrial and free-radical metabolism. The discovery of the first gene mutation for Parkinson's disease, in alpha-synuclein, ushered in the genetic era for the disease and the subsequent finding of several gene mutations causing parkinsonism, 15 at the time of writing. Technological advances both in sequencing technology and software analysis have allowed association studies of sufficiently large size accurately to describe genes conferring an increased risk for Parkinson's disease. What has been so surprising is the convergence of these 2 separate disciplines (biochemistry and genetics) in terms of reinforcing the importance of the same pathways (ie, mitochondrial dysfunction and free-radical metabolism). Other pathways are also important in pathogenesis, including protein turnover, inflammation, and post-translational modification, particularly protein phosphorylation and ubiquitination. However, even these additional pathways overlap with each other and with those of mitochondrial dysfunction and oxidative stress. This review explores these concepts with particular relevance to mitochondrial involvement.
在过去的25年里，我们对帕金森病的病因和发病机制的理解取得了显著进展。对帕金森病患者死后大脑进行详细生化分析的能力，使得线粒体和自由基代谢缺陷得以识别。帕金森病首个基因突变（α-突触核蛋白基因突变）的发现，开启了该疾病的基因研究时代，随后又发现了多个导致帕金森症的基因突变，在撰写本文时已达15个。测序技术和软件分析方面的技术进步，使得大规模关联研究能够准确描述增加帕金森病患病风险的基因。令人惊讶的是，这两个独立学科（生物化学和遗传学）在强化相同通路（即线粒体功能障碍和自由基代谢）的重要性方面达成了一致。其他通路在发病机制中也很重要，包括蛋白质周转、炎症和翻译后修饰，特别是蛋白质磷酸化和泛素化。然而，即使这些额外的通路彼此之间以及与线粒体功能障碍和氧化应激的通路也相互重叠。本综述探讨了这些概念，尤其关注线粒体的参与情况。
