A full understanding of Parkinson's Disease etiopathogenesis and of the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. A multiple-hit hypothesis has been proposed, which may explain the convergence of familial, environmental and idiopathic forms of the disease. Among the various determinants of the degeneration of the neurons in Substantia Nigra pars compacta, in this review we will focus on the endotoxicity associated to dopamine dyshomeostasis. In particular, we will discuss the relevance of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in the catechol-induced neurotoxicity. Indeed, the synergy between the catechol and the aldehyde moieties of DOPAL exacerbates its reactivity, resulting in modification of functional protein residues, protein aggregation, oxidative stress and cell death. Interestingly, αSynuclein, whose altered proteostasis is a recurrent element in Parkinson's Disease pathology, is considered a preferential target of DOPAL modification. DOPAL triggers αSynuclein oligomerization leading to synapse physiology impairment. Several factors can be responsible for DOPAL accumulation at the pre-synaptic terminals, i.e. dopamine leakage from synaptic vesicles, increased rate of dopamine conversion to DOPAL by upregulated monoamine oxidase and decreased DOPAL degradation by aldehyde dehydrogenases. Various studies report the decreased expression and activity of aldehyde dehydrogenases in parkinsonian brains, as well as genetic variants associated to increased risk in developing the pathology. Thus, we discuss how the deregulation of these enzymes might be considered a contributing element in the pathogenesis of Parkinson's Disease or a down-stream effect. Finally, we propose that a better understanding of the impaired dopamine metabolism in Parkinson's Disease would allow a more refined patients stratification and the design of more targeted and successful therapeutic strategies.

中文翻译：

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帕金森氏病发病机理中的多巴胺代谢受损。

对帕金森氏病的发病机制和黑纹状体多巴胺能神经元优先脆弱性的原因的充分理解仍然是一个未解之谜。已经提出了多重打击假说，该假说可以解释该疾病的家族性，环境性和特发性形式的趋同。在黑质致密性黑质神经元变性的各种决定因素中，本文将重点研究与多巴胺动态平衡有关的内毒素。特别是，我们将讨论反应性多巴胺代谢产物3,4-二羟基苯基乙醛（DOPAL）在邻苯二酚诱导的神经毒性中的相关性。实际上，DOPAL的邻苯二酚和醛基之间的协同作用会加剧其反应性，从而导致功能性蛋白质残基的修饰，蛋白质聚集，氧化应激和细胞死亡。有趣的是，αSynuclein的蛋白稳态改变是帕金森氏病病理学中的复发因素，被认为是DOPAL修饰的优先靶标。DOPAL触发αSynuclein寡聚，导致突触生理损伤。几个因素可能导致DOPAL在突触前末端积累，例如，突触小泡中的多巴胺泄漏，单胺氧化酶上调导致多巴胺转化为DOPAL的速率增加以及醛脱氢酶降低DOPAL降解。各种研究报道了帕金森氏脑中醛脱氢酶的表达和活性下降，以及与发展病理风险增加相关的遗传变异。因此，我们讨论了如何将这些酶的失调视为帕金森氏病发病机理或下游效应的一个促成因素。最后，我们建议更好地了解帕金森氏病中多巴胺代谢受损的情况，可以使患者更加精细，并设计出更有针对性和成功的治疗策略。