Drug targets from genetics: α-synuclein.
Drug targets from genetics: α-synuclein.
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DOI：
10.2174/187152711797247867
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发表时间：
2011-09-01
期刊：
影响因子：
--
通讯作者：
McLean PJ
中科院分区：
文献类型：
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作者：
Danzer KM;McLean PJ
帕金森病（PD）研究中的关键问题之一是确定特定的毒性致病部分。在PD中，α-突触核蛋白（αsyn）的突变或编码αsyn的SNCA基因的增殖导致细胞包涵体、细胞死亡和脑功能障碍的表型。虽然历史观点一直认为含有α-syn的宏观聚集体是有毒物质，但在过去几年中出现的证据表明，较小的可溶性物质-可能含有错误折叠的α-syn的低聚物-实际上是有毒部分，纤维状内含物甚至可能是细胞解毒途径，危害较小。如果αsyn的可溶性错误折叠种类是毒性部分，那么降解错误折叠αsyn的细胞机制将是神经保护性的，并且是药物开发的合理目标。在这篇综述中，我们将讨论αsyn毒性的基本机制，包括寡聚体形成，氧化应激和降解途径，并考虑合理的治疗策略，可能有可能预防或停止αsyn诱导的PD发病机制。
One of the critical issues in Parkinson disease (PD) research is the identity of the specific toxic, pathogenic moiety. In PD, mutations in alpha-synuclein (αsyn) or multiplication of the SNCA gene encoding αsyn, result in a phenotype of cellular inclusions, cell death, and brain dysfunction. While the historical point of view has been that the macroscopic aggregates containing αsyn are the toxic species, in the last several years evidence has emerged that suggests instead that smaller soluble species - likely oligomers containing misfolded αsyn - are actually the toxic moiety and that the fibrillar inclusions may even be a cellular detoxification pathway and less harmful. If soluble misfolded species of αsyn are the toxic moieties, then cellular mechanisms that degrade misfolded αsyn would be neuroprotective and a rational target for drug development. In this review we will discuss the fundamental mechanisms underlying αsyn toxicity including oligomer formation, oxidative stress, and degradation pathways and consider rational therapeutic strategies that may have the potential to prevent or halt αsyn induced pathogenesis in PD.