Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Semin Neurol. 2020 Oct;40(5):502-514. doi: 10.1055/s-0040-1713874. Epub 2020 Sep 9.
The catecholamines dopamine and norepinephrine are key central neurotransmitters that participate in many neurobehavioral processes and disease states. Norepinephrine is also the main neurotransmitter mediating regulation of the circulation by the sympathetic nervous system. Several neurodegenerative disorders feature catecholamine deficiency. The most common is Parkinson's disease (PD), in which putamen dopamine content is drastically reduced. PD also entails severely decreased myocardial norepinephrine content, a feature that characterizes two other Lewy body diseases-pure autonomic failure and dementia with Lewy bodies. It is widely presumed that tissue catecholamine depletion in these conditions results directly from loss of catecholaminergic neurons; however, as highlighted in this review, there are also important functional abnormalities in extant residual catecholaminergic neurons. We refer to this as the "sick-but-not-dead" phenomenon. The malfunctions include diminished dopamine biosynthesis via tyrosine hydroxylase (TH) and L-aromatic-amino-acid decarboxylase (LAAAD), inefficient vesicular sequestration of cytoplasmic catecholamines, and attenuated neuronal reuptake via cell membrane catecholamine transporters. A unifying explanation for catecholaminergic neurodegeneration is autotoxicity exerted by 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediate in cytoplasmic dopamine metabolism. In PD, putamen DOPAL is built up with respect to dopamine, associated with a vesicular storage defect and decreased aldehyde dehydrogenase activity. Probably via spontaneous oxidation, DOPAL potently oligomerizes and forms quinone-protein adducts with ("quinonizes") α-synuclein (AS), a major constituent in Lewy bodies, and DOPAL-induced AS oligomers impede vesicular storage. DOPAL also quinonizes numerous intracellular proteins and inhibits enzymatic activities of TH and LAAAD. Treatments targeting DOPAL formation and oxidation therefore might rescue sick-but-not-dead catecholaminergic neurons in Lewy body diseases.
儿茶酚胺多巴胺和去甲肾上腺素是参与许多神经行为过程和疾病状态的关键中枢神经递质。去甲肾上腺素也是交感神经系统调节循环的主要神经递质。几种神经退行性疾病都存在儿茶酚胺缺乏。最常见的是帕金森病（PD），其中壳核多巴胺含量急剧下降。PD 还伴有心肌去甲肾上腺素含量严重降低，这是另两种路易体疾病-单纯自主神经衰竭和路易体痴呆的特征。人们普遍认为，这些情况下组织儿茶酚胺的耗竭直接源于儿茶酚胺能神经元的丧失；然而，正如本文所强调的，现存的剩余儿茶酚胺能神经元也存在重要的功能异常。我们称之为“病态但未死亡”现象。这些功能障碍包括酪氨酸羟化酶（TH）和 L-芳香族氨基酸脱羧酶（LAAAD）减少多巴胺生物合成、细胞质儿茶酚胺的囊泡摄取效率降低、以及通过细胞膜儿茶酚胺转运体减弱神经元再摄取。儿茶酚胺能神经元退行性变的一个统一解释是 3,4-二羟基苯乙酸（DOPAL）的自毒性，它是细胞质多巴胺代谢中的必需中间产物。在 PD 中，壳核 DOPAL 相对于多巴胺而积累，与囊泡储存缺陷和醛脱氢酶活性降低有关。可能通过自发氧化，DOPAL 强烈地寡聚化并与路易体中的主要成分α-突触核蛋白（AS）形成醌-蛋白加合物（“醌化”），并且 DOPAL 诱导的 AS 寡聚物阻碍囊泡储存。DOPAL 还醌化许多细胞内蛋白并抑制 TH 和 LAAAD 的酶活性。因此，针对 DOPAL 形成和氧化的治疗方法可能挽救路易体疾病中病态但未死亡的儿茶酚胺能神经元。
