UCL Institute of Neurology, Department of Molecular Neuroscience, Queen Square, London WC1N 3BG, UK.
Expert Opin Ther Targets. 2010 May;14(5):497-511. doi: 10.1517/14728221003730434.
With improvements in life expectancy over the past decades, the incidence of neurodegenerative disease has dramatically increased and new therapeutic strategies are urgently needed. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders.
This review examines the role of mitochondrial dysfunction in neurodegeneration, drawing examples from common diseases such as Alzheimer's disease and rarer familial disorders such as Charcot-Marie-Tooth. The review is provided in two parts. In part I we discussed the mitochondrial defects which have been most extensively researched (oxidative stress, bioenergetic dysfunction, calcium mishandling). We focus now on those defects which have more recently been implicated in neurodegeneration; in mitochondrial fusion/fission, protein import, protein quality control, kinase signalling and opening of the permeability transition pore.
An examination of mitochondrial defects observed in neurodegeneration, and existing and possible future therapies to target these defects.
The mitochondrially-targeted therapeutics that have reached clinical trials so far have produced encouraging but largely inconclusive results. Increasing understanding of mitochondrial dysfunction has, however, led to preclinical work focusing on novel approaches, which has generated exciting preliminary data.
随着过去几十年来预期寿命的提高，神经退行性疾病的发病率急剧增加，迫切需要新的治疗策略。一种可能的方法是针对线粒体功能障碍，这与许多神经退行性疾病的发病机制有关。
本篇综述考察了线粒体功能障碍在神经退行性变中的作用，从阿尔茨海默病等常见疾病和夏科-马里-图什等罕见家族性疾病中举例说明。综述分为两部分。在第一部分中，我们讨论了研究最多的线粒体缺陷（氧化应激、生物能量功能障碍、钙处理不当）。我们现在关注的是那些最近与神经退行性变有关的缺陷；在线粒体融合/裂变、蛋白质导入、蛋白质质量控制、激酶信号转导和通透性转换孔的开放。
对神经退行性变中观察到的线粒体缺陷以及现有和可能的未来针对这些缺陷的治疗方法的检查。
到目前为止，已经进入临床试验的靶向线粒体的治疗方法产生了令人鼓舞但基本上没有定论的结果。然而，对线粒体功能障碍的认识不断提高，导致了专注于新方法的临床前工作，这些方法产生了令人兴奋的初步数据。
