帕金森病(PD)的特征在于氨基酸序列中的异常翻译后修饰(PTM)和α-突触核蛋白(α-Syn)蛋白的聚集。通常认为多巴胺能(DAergic)神经元中的多巴胺(DA)代谢物促进有毒的α-Syn寡聚体和原原纤维的聚集,而DA抑制有毒纤维的形成,甚至降解有毒纤维。因此,DA代谢产物与α-Syn寡聚体相互作用的研究是当前神经科学研究的热点之一,因为这种效应可能与PD中的选择性DA能神经元丢失直接相关。已经报道了DA代谢物诱导的α-Syn寡聚物的几种机制。i)DA的自动氧化或酶促氧化过程中释放的活性氧(ROS)通过氨基酸残基的氧化导致错误折叠而改变了α-Syn的结构,ii)氧化的DA代谢物通过共价或非共价结合直接与α-Syn相互作用,导致低聚物的形成,iii)DA与脂质或自噬相关蛋白相互作用以降低α-Syn聚集体的降解效率。然而,对于DA和α-Syn之间的相互作用,没有明确的机制。然而,认为α-Syn序列的赖氨酸(Lys)侧链是寡聚体形成的初始触发位点。在这里,我们综述了α-Syn的Lys侧链与多巴胺-邻醌(DAQ)等DA代谢产物相互作用的不同化学机制,多巴胺铬(DAC),多巴胺醛(DOPAL)和神经黑色素。本文还提供了二价Cu2离子对DA代谢产物诱导的α-Syn低聚物的促进作用以及抗氧化剂谷胱甘肽(GSH)的抑制作用。
Parkinson\'s disease (PD) is characterized by an abnormal post-translational modifications (PTM) in amino acid sequence and aggregation of alpha-synuclein (α-Syn) protein. It is generally believed that dopamine (DA) metabolite in dopaminergic (DAergic) neurons promotes the aggregation of toxic α-Syn oligomers and protofibrils, whereas DA inhibits the formation of toxic fibers and even degrades the toxic fibers. Therefore, the study on interaction between DA metabolites and α-Syn
oligomers is one of the current hot topics in neuroscience, because this effect may have direct relevance to the selective DAergic neuron loss in PD. Several mechanisms have been reported for DA metabolites induced α-Syn
oligomers viz. i) The reactive oxygen species (ROS) released during the auto-oxidation or enzymatic oxidation of DA changes the structure of α-Syn by the oxidation of amino acid residue leading to misfolding, ii) The oxidized DA metabolites directly interact with α-Syn through covalent or non-covalent bonding leading to the formation of oligomers, iii) DA interacts with lipid or autophagy related proteins to decreases the degradation efficiency of α-Syn aggregates. However, there is no clear-cut mechanism proposed for the interaction between DA and α-Syn. However, it is believed that the lysine (Lys) side chain of α-Syn sequence is the initial trigger site for the oligomer formation. Herein, we
review different chemical mechanism involved during the interaction of Lys side chain of α-Syn with DA metabolites such as dopamine-o-quinone (DAQ), dopamine-chrome (DAC), dopamine-aldehyde (DOPAL) and neuromelanin. This
review also provides the promotive effect of divalent Cu2+ ions on DA metabolites induced α-Syn
oligomers and its inhibition effect by antioxidant glutathione (GSH).