Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives
Slowing of neurodegeneration in Parkinson's disease and Huntington's disease: future therapeutic perspectives
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DOI：
10.1016/s0140-6736(14)61010-2
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发表时间：
2014-08-09
期刊：
影响因子：
168.9
通讯作者：
Bezard, Erwan
中科院分区：
文献类型：
--
作者：
Schapira, Anthony H. V.;Olanow, C. Warren;Bezard, Erwan
我们对导致帕金森病和亨廷顿病细胞功能障碍和死亡的途径的理解取得了一些重要进展。这些进展是通过对死后大脑的直接分析和对这些疾病的遗传原因的生物学后果的研究来实现的。迄今为止涉及的一些途径包括线粒体功能障碍、氧化应激、激酶途径、钙失调、炎症、蛋白质处理和朊病毒样过程。有趣的是，这些途径似乎在这两种疾病的发病机制中都很重要，并导致了旨在减缓或逆转其病程的候选干预措施的分子靶标的确定。我们回顾了帕金森病和亨廷顿病神经保护假定疗法的一些最新进展，以及未来可能利用的潜在目标。尽管我们需要克服重要的障碍，特别是在临床试验设计方面，但我们提出了一些值得进一步研究的目标途径。在帕金森病中，这些靶标包括可能改善线粒体功能或增加有缺陷的线粒体降解的药物、激酶抑制剂、钙通道阻滞剂以及干扰 α-突触核蛋白错误折叠、模板化和传输的方法。在亨廷顿病中，策略还可能针对线粒体生物能和周转、预防蛋白质失调、破坏亨廷顿蛋白和 p53 或亨廷顿蛋白相互作用蛋白 1 之间的相互作用以减少细胞凋亡，以及在核酸和蛋白质水平上干扰突变亨廷顿蛋白的表达。
Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome important hurdles, especially in terms of clinical trial design, we propose several target pathways that merit further study. In Parkinson's disease, these targets include agents that might improve mitochondrial function or increase degradation of defective mitochondria, kinase inhibitors, calcium channel blockers, and approaches that interfere with the misfolding, templating, and transmission of alpha-synuclein. In Huntington's disease, strategies might also be directed at mitochondrial bioenergetics and turnover, the prevention of protein dysregulation, disruption of the interaction between huntingtin and p53 or huntingtin-interacting protein 1 to reduce apoptosis, and interference with expression of mutant huntingtin at both the nucleic acid and protein levels.