Several neurodegenerative diseases involve loss of catecholamine neurons-Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of "autotoxicity"-inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the "catecholaldehyde hypothesis" for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis.

中文翻译：

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儿茶酚胺自毒性。对帕金森病及相关疾病的药理学和治疗学的影响。


一些神经退行性疾病涉及儿茶酚胺神经元的丧失——帕金森病就是一个典型的例子。儿茶酚胺神经元在神经系统中很少见，为什么它们在帕金森病和相关疾病中很脆弱一直是个谜。越来越多的证据支持“自毒性”的概念——儿茶酚胺及其代谢物在产生它们的细胞中具有固有的细胞毒性。根据帕金森病发病机制的“儿茶酚醛假说”，3,4-二羟基苯乙醛（DOPAL）（多巴胺的儿茶酚醛代谢物）的长期积累增加，会导致或促成多巴胺能神经元的最终死亡。路易体是 PD 的神经病理学标志，含有沉淀的 α-突触核蛋白。 α-突触核蛋白在儿茶酚胺能神经元细胞质中沉淀的倾向的基础也一直是个谜。由于 DOPAL 有效寡聚和聚集 α-突触核蛋白，儿茶酚醛假说提供了路易体疾病中 α-突触核蛋白病和儿茶酚胺神经元损失之间的联系。这里提出的概念是，DOPAL 和 α-突触核蛋白是相互作用的稳态系统的复杂关系中的节点。几个过程的功能障碍，包括细胞质儿茶酚胺的囊泡隔离减少、乙醛脱氢酶活性降低和α-突触核蛋白寡聚化，导致从负反馈调节提供的稳定性转变为由正反馈调节引起的不稳定、退化和系统故障。反馈循环。这些功能障碍是由遗传倾向、环境暴露、压力和时间的多种组合造成的。 儿茶酚胺自毒性的概念对于治疗、疾病改变和预防具有多种意义。相反，疾病修饰临床试验将为儿茶酚醛假说提供关键检验。