Direct binding and functional coupling of α-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis
Direct binding and functional coupling of α-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis
复制标题
DOI：
10.1096/fj.00-0334com
复制
发表时间：
2001-04-01
期刊：
影响因子：
4.8
通讯作者：
Niznik, HB
中科院分区：
文献类型：
--
作者：
Lee, FJS;Liu, F;Niznik, HB
α-突触核蛋白（一种在突触前末梢高度富集的蛋白质）的突变与帕金森病（PD）家族形式的表达有关，而天然α-突触核蛋白是PD和其它神经变性疾病特征性的神经元内包涵体的主要成分.尽管人α-突触核蛋白的过表达诱导多巴胺能神经末梢变性，但α-突触核蛋白促进这些途径变性的分子机制仍然是谜，我们在这里报道，在神经元和共转染细胞中，α-突触核蛋白通过α-突触核蛋白的非A β淀粉样蛋白组分与羧基-β淀粉样蛋白组分的直接结合，与突触前人类多巴胺转运蛋白（hDAT）复合。hDAT的末端尾，α-突触核蛋白-hDAT复合物的形成促进DAT的膜聚集，从而加速细胞多巴胺摄取和多巴胺诱导的细胞凋亡。由于PD中多巴胺能神经元的选择性脆弱性部分归因于氧化应激，这是由于突触前DAT导致多巴胺或多巴胺样分子的细胞过度积累，这些数据提供了对这两种蛋白质的活性可能引起这一过程的模式的机械见解。
Mutations in alpha -synuclein, a protein highly enriched in presynaptic terminals, have been implicated in the expression of familial forms of Parkinson's disease (PD) whereas native alpha -synuclein is a major component of intraneuronal inclusion bodies characteristic of PD and other neurodegenerative disorders. Although overexpression of human a-synuclein induces dopaminergic nerve terminal degeneration, the molecular mechanism by which alpha -synuclein contributes to the degeneration of these pathways remains enigmatic, We report here that alpha -synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non-A beta amyloid component of alpha -synuclein to the carboxyl-terminal tail of the hDAT, alpha -Synuclein-hDAT complex formation facilitates the membrane clustering of the DAT, thereby accelerating cellular dopamine uptake and dopamine-induced cellular apoptosis, Since the selective vulnerability of dopaminergic neurons in PD has been ascribed in part to oxidative stress as a result of the cellular overaccumulation of dopamine or dopamine-like molecules by the presynaptic DAT, these data provide mechanistic insight into the mode by which the activity of these two proteins may give rise to this process.