Instituto Teófilo Hernando, Departamento. de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
Instituto de Investigación Sanitaria, Hospital Universitario de La Princesa, 28006 Madrid, Spain.
Int J Mol Sci. 2020 Mar 12;21(6):1946. doi: 10.3390/ijms21061946.
Synaptic disruption and altered neurotransmitter release occurs in the brains of patients and in murine models of neurodegenerative diseases (NDDs). During the last few years, evidence has accumulated suggesting that the sympathoadrenal axis is also affected as disease progresses. Here, we review a few studies done in adrenal medullary chromaffin cells (CCs), that are considered as the amplifying arm of the sympathetic nervous system; the sudden fast exocytotic release of their catecholamines-stored in noradrenergic and adrenergic cells-plays a fundamental role in the stress fight-or-flight response. Bulk exocytosis and the fine kinetics of single-vesicle exocytotic events have been studied in mouse models carrying a mutation linked to NDDs. For instance, in R6/1 mouse models of Huntington's disease (HD), mutated huntingtin is overexpressed in CCs; this causes decreased quantal secretion, smaller quantal size and faster kinetics of the exocytotic fusion pore, pore expansion, and closure. This was accompanied by decreased sodium current, decreased acetylcholine-evoked action potentials, and attenuated [Ca]c transients with faster Ca clearance. In the SOD1 mouse model of amyotrophic lateral sclerosis (ALS), CCs exhibited secretory single-vesicle spikes with a slower release rate but higher exocytosis. Finally, in the APP/PS1 mouse model of Alzheimer's disease (AD), the stabilization, expansion, and closure of the fusion pore was faster, but the secretion was attenuated. Additionally, α-synuclein that is associated with Parkinson's disease (PD) decreases exocytosis and promotes fusion pore dilation in adrenal CCs. Furthermore, Huntington-associated protein 1 (HAP1) interacts with the huntingtin that, when mutated, causes Huntington's disease (HD); HAP1 reduces full fusion exocytosis by affecting vesicle docking and controlling fusion pore stabilization. The alterations described here are consistent with the hypothesis that central alterations undergone in various NDDs are also manifested at the peripheral sympathoadrenal axis to impair the stress fight-or-flight response in patients suffering from those diseases. Such alterations may occur: (i) primarily by the expression of mutated disease proteins in CCs; (ii) secondarily to stress adaptation imposed by disease progression and the limitations of patient autonomy.
在神经退行性疾病（NDDs）患者和啮齿动物模型中，突触破坏和神经递质释放改变发生在大脑中。在过去的几年中，有证据表明，随着疾病的进展，交感肾上腺轴也受到影响。在这里，我们回顾了一些在肾上腺髓质嗜铬细胞（CCs）中进行的研究，这些细胞被认为是交感神经系统的放大臂；它们储存的儿茶酚胺的突然快速胞吐释放——在应激反应的战斗或逃跑中起着至关重要的作用。在携带与 NDDs 相关突变的小鼠模型中，已经研究了胞吐的整体释放和单个囊泡胞吐事件的精细动力学。例如，在亨廷顿病（HD）的 R6/1 小鼠模型中，突变型亨廷顿蛋白在 CCs 中过度表达；这导致量子分泌减少、量子大小减小以及胞吐融合孔、孔扩张和闭合的动力学加快。这伴随着钠电流减少、乙酰胆碱诱发的动作电位减少以及钙清除更快的 [Ca]c 瞬变衰减。在肌萎缩侧索硬化症（ALS）的 SOD1 小鼠模型中，CCs 表现出分泌性单囊泡尖峰，其释放速率较慢，但胞吐作用较高。最后，在阿尔茨海默病（AD）的 APP/PS1 小鼠模型中，融合孔的稳定、扩张和闭合更快，但分泌减少。此外，与帕金森病（PD）相关的α-突触核蛋白降低了肾上腺 CCs 的胞吐作用并促进融合孔扩张。此外，与亨廷顿病相关的蛋白 1（HAP1）与突变导致亨廷顿病（HD）的亨廷顿蛋白相互作用；HAP1 通过影响囊泡 docking 并控制融合孔稳定性来减少完全融合的胞吐作用。这里描述的改变与这样一种假设一致，即各种 NDD 中发生的中枢改变也表现在周围的交感肾上腺轴上，从而损害患有这些疾病的患者的应激反应。这种改变可能发生：（i）主要是由于 CCs 中突变疾病蛋白的表达；（ii）其次是由于疾病进展和患者自主性限制带来的应激适应。
