中国神经再生研究(英文版) ›› 2015, Vol. 10 ›› Issue (8): 1225-1227.doi: 10.4103/1673-5374.162750

• 观点:退行性病与再生 • 上一篇    下一篇

星形胶质细胞介导多巴胺能神经元保护的新机制

  

  • 收稿日期:2015-05-20 出版日期:2015-08-24 发布日期:2015-08-24

A new mechanism for protection of dopaminergic neurons mediated by astrocytes

Juan Segura-Aguilar   

  • Received:2015-05-20 Online:2015-08-24 Published:2015-08-24
  • Contact: Juan Segura-Aguilar, Ph.D., jsegura@med.uchile.cl.

摘要:

很长一段时间内,有关参与黑质纹状体系统的退行性过程机制在帕金森病中一直是未被解答的问题,并导致含神经黑素的多巴胺能神经元丧失。目前已发现的帕金森病家族形式关联基因包括:α突触核蛋白,parkin,DJ-1,PINK-1,LRRK-2,ATP13A2,PINK-1等,这对基础研究领域是一项重大贡献,同时我们也应了解这些蛋白在散发性帕金森病中的作用。学科界有一种广泛共识,即黑质纹状体内含神经黑素的多巴胺能神经元会凋亡,并涉及到线粒体功能障碍,蛋白质降解功能障碍和α突触核蛋白到神经毒性低聚物的积累,以及氧化应激,神经炎症和内质网应激。现在的问题是认定触发这些机制的神经毒素身份,以及这些机制之间可能存在的协同作用。有一点或许是合理的,即参与黑质纹状体多巴胺能系统退行性过程的神经毒素必须是内源性来源,因为帕金森病的神经退行性过程进展很慢,当60-70%的含神经黑素的多巴胺能神经元凋亡是通常需要数年时间。来源于多巴胺氧化的O-醌类物质可能是帕金森病中含神经黑素多巴胺能神经元损失的主要原因,因为这些神经元需要氧化成O-醌类物质以产生神经黑素。有趣的是,已有报道证实了多巴胺氧化产生的O-醌类物质会诱导线粒体功能障碍,α-突触核蛋白聚集到神经毒性寡聚体等。

Abstract:

A new mechanism for dopaminergic neurons protection mediated by astrocytes For a long time, the question about the mechanism involved in the degenerative process of the nigrostriatal system in Parkinson’s disease (PD), resulting in the loss of dopaminergic neurons containing neuromelanin, has remained open. The discovery of genes associated with familial forms of PD, such as α-synuclein (SNCA), parkin, DJ-1, PINK-1, LRRK-2, ATP13A2, PINK-1 and others resulted in important input into the basic research in this field with the aim of understanding the role of these proteins in sporadic PD. In the scientific community, there is a general agreement that the loss of dopaminergic neurons containing neuromelanin in the nigrostriatal system involves mitochondria dysfunction, protein degradation dysfunction, and SNCA aggregation in neurotoxic oligomers, oxidative stress, neuroinflammation and endoplasmic reticulum stress.
Prof. Juan Segura-Aguilar (University of Chile, Chile) proposed that the neurotoxin involved in the degenerative process of the dopaminergic nigrostriatal system must be of endogenous origin, since the progression of the neurodegenerative process in PD is very slow and takes years for the development of motor symptoms, when up to 60–70% of dopaminergic neurons containing neuromelanin are lost. The slow progression of the degenerative process in PD contrasts with the extremely rapid degeneration observed in humans who are injected with drugs containing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), who after only 3 days develop severe motor symptoms. The possibility that o-quinones derived from dopamine oxidation are responsible for the loss of dopaminergic neurons containing neuromelanin in PD is supported by the fact that these neurons require dopamine oxidation to o-quinones to generate neuromelanin. Interestingly, o-quinones generated during dopamine oxidation have been reported to induce mitochondria dysfunction, SNCA aggregation in neurotoxic oligomers, protein degradation dysfunction of both proteasomal and lysosomal systems and oxidative stress.