Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Antioxid Redox Signal. 2011 Apr 1;14(7):1289-301. doi: 10.1089/ars.2010.3521. Epub 2010 Dec 15.
Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cell-specific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.
帕金森病（PD）是一个全球性的健康问题，困扰着数以百万计的老年人口。作用于大多数或所有细胞类型的因素（全细胞因素），特别是遗传突变和环境毒素，一直主导着疾病病因的公众讨论。尽管有强有力的证据支持疾病风险与这些因素之间存在关联，但如果没有特定于细胞的因素，神经元病理学和细胞丢失的模式就很难解释。本文重点介绍了最近的研究表明，PD 中风险最大的神经元——黑质致密部多巴胺神经元——具有独特的生理表型，这可能导致它们易受损伤。自主起搏期间 L 型钙通道的开放导致持续的钙进入黑质致密部多巴胺神经元的细胞质，导致线粒体氧化应激升高，并易受用于创建 PD 动物模型的毒素的影响。这种特定于细胞的应激可能会增加广泛挑战线粒体或蛋白质稳态能力的全细胞因素的负面后果。具有良好耐受性、可口服给予的 L 型钙通道拮抗剂的可用性表明了一种新的神经保护策略，该策略可能补充目前在疾病早期阶段提高线粒体功能的尝试。
