Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016, USA.
Department of Medical Neurobiology, Institute of Medical Research Israel - Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, 9112102 Jerusalem, Israel.
Pharmacol Ther. 2024 Aug;260:108683. doi: 10.1016/j.pharmthera.2024.108683. Epub 2024 Jun 29.
Parkinson's disease (PD) is diagnosed by its cardinal motor symptoms that are associated with the loss of dopamine neurons in the substantia nigra pars compacta (SNc). However, PD patients suffer from various non-motor symptoms years before diagnosis. These prodromal symptoms are thought to be associated with the appearance of Lewy body pathologies (LBP) in brainstem regions such as the dorsal motor nucleus of the vagus (DMV), the locus coeruleus (LC) and others. The neurons in these regions that are vulnerable to LBP are all slow autonomous pacemaker neurons that exhibit elevated oxidative stress due to their perpetual influx of Ca ions. Aggregation of toxic α-Synuclein (aSyn) - the main constituent of LBP - during the long prodromal period challenges these vulnerable neurons, presumably altering their biophysics and physiology. In contrast to pathophysiology of late stage parkinsonism which is well-documented, little is known about the pathophysiology of the brainstem during prodromal PD. In this review, we discuss ion channel dysregulation associated with aSyn aggregation in brainstem pacemaker neurons and their cellular responses to them. While toxic aSyn elevates oxidative stress in SNc and LC pacemaker neurons and exacerbates their phenotype, DMV neurons mount an adaptive response that mitigates the oxidative stress. Ion channel dysregulation and cellular adaptations may be the drivers of the prodromal symptoms of PD. For example, selective targeting of toxic aSyn to DMV pacemakers, elevates the surface density of K channels, which slows their firing rate, resulting in reduced parasympathetic tone to the gastrointestinal tract, which resembles the prodromal PD symptoms of dysphagia and constipation. The divergent responses of SNc & LC vs. DMV pacemaker neurons may explain why the latter outlive the former despite presenting LBPs earlier. Elucidation the brainstem pathophysiology of prodromal PD could pave the way for physiological biomarkers, earlier diagnosis and novel neuroprotective therapies for PD.
帕金森病 (PD) 的诊断依据是其主要运动症状，这些症状与黑质致密部 (SNc) 中的多巴胺神经元丧失有关。然而，PD 患者在诊断前多年就会遭受各种非运动症状的困扰。这些前驱症状被认为与脑干区域（如迷走神经背核 (DMV)、蓝斑核 (LC) 等）中的路易体病理学 (LBP) 的出现有关。这些易受 LBP 影响的区域中的神经元都是自主慢节奏的起搏神经元，由于其钙离子的持续流入，会表现出升高的氧化应激。在漫长的前驱期内，有毒的α-突触核蛋白 (aSyn)——LBP 的主要成分——的聚集，对这些易受影响的神经元构成了挑战，可能改变了它们的生物物理和生理学特性。与帕金森病后期的病理生理学已有充分记录相比，前驱期 PD 中脑干的病理生理学知之甚少。在这篇综述中，我们讨论了与脑干起搏神经元中 aSyn 聚集相关的离子通道失调及其对这些神经元的细胞反应。虽然有毒的 aSyn 会增加 SNc 和 LC 起搏神经元中的氧化应激，并加剧其表型，但 DMV 神经元会产生适应性反应，减轻氧化应激。离子通道失调和细胞适应可能是 PD 前驱症状的驱动因素。例如，将有毒的 aSyn 选择性靶向 DMV 起搏器，会增加 K 通道的表面密度，从而降低其放电频率，导致胃肠道的副交感神经张力降低，类似于 PD 前驱期的吞咽困难和便秘症状。SNc 和 LC 与 DMV 起搏神经元的不同反应可能解释了为什么后者尽管更早出现 LBPs，但比前者更长寿。阐明前驱期 PD 的脑干病理生理学可能为生理生物标志物、早期诊断和 PD 的新型神经保护疗法铺平道路。
