The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know.
The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know.
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DOI：
10.3390/ijms22115999
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发表时间：
2021-06-01
影响因子：
5.6
通讯作者：
Goldstein DS
中科院分区：
文献类型：
--
作者：
Goldstein DS
3，4-二羟基苯乙醛(DOPAL)是儿茶醛假说在帕金森氏病和其他路易体疾病发病机制中的核心。儿茶酚醛是通过作用于细胞质多巴胺的单胺氧化酶(MAO)催化氧化脱氨而产生的。DOPAL是自毒的，因为它可以伤害产生DOPAL的相同细胞。正常情况下，DOPAL是通过乙醛脱氢酶(ALDH)介导的转化为3，4-二羟基苯乙酸(DOPAC)来解毒的，后者会迅速离开神经元。遗传、环境或药物诱导的ALDH形成DOPAL的操作会促进儿茶酚胺能神经退化。一个源自儿茶醛假说的概念认为，DOPAL与路易小体的主要成分--α-突触核蛋白(αS)之间存在有害的相互作用。DOPAL能有效地寡聚αS，而αS寡聚体阻碍囊泡和线粒体功能，将细胞质多巴胺的命运转向MAO催化的形成DOPAL破坏稳定的恶性循环。DOPAL和DOPAL诱导的错误折叠蛋白的直接和间接作用可以“冻结”神经元内反应，其可塑性是神经元动态平衡所必需的。DOPAL的毒性在多大程度上是通过与αS的相互作用介导的，反之亦然，人们对此知之甚少。由于存在大量的次要效应，如通过MAO抑制增强多巴胺的自发氧化，儿茶酚醛假说在动物模型中一直没有得到充分的验证。与儿茶酚醛假说相关的遗传学、情绪应激、环境因素以及与众多蛋白质的相互作用的临床病理生理学意义有待于未来的研究。神经细胞内儿茶酚胺代谢的复杂性似乎需要一种计算模型方法来阐明临床发病机制并设计基于病理生理学的个体化治疗方法。
3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.
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影响因子：
2.4
作者：
Bisaglia M;Greggio E;Maric D;Miller DW;Cookson MR;Bubacco L
通讯作者：
Bubacco L
DOI：
10.1007/bf02156938
发表时间：
1957-01-01
期刊：
EXPERIENTIA
影响因子：
--
作者：
BLASCHKO, H
通讯作者：
BLASCHKO, H
影响因子：
12.6
作者：
Cai H;Liu G;Sun L;Ding J
通讯作者：
Ding J
DOI：
10.1126/science.aam9080
发表时间：
2017-09-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Burbulla LF;Song P;Mazzulli JR;Zampese E;Wong YC;Jeon S;Santos DP;Blanz J;Obermaier CD;Strojny C;Savas JN;Kiskinis E;Zhuang X;Krüger R;Surmeier DJ;Krainc D
通讯作者：
Krainc D
影响因子：
4.1
作者：
Anderson, David G.;Florang, Virginia R.;Doorn, Jonathan A.
通讯作者：
Doorn, Jonathan A.