A Molecular Basis for the Increased Vulnerability of Substantia Nigra Dopamine Neurons in Aging and Parkinson's Disease
A Molecular Basis for the Increased Vulnerability of Substantia Nigra Dopamine Neurons in Aging and Parkinson's Disease
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DOI：
10.1002/mds.22801
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发表时间：
2010-01-01
影响因子：
8.6
通讯作者：
Surmeier, D. James
中科院分区：
文献类型：
--
作者：
Chan, C. Savio;Gertler, Tracy S.;Surmeier, D. James
帕金森病（Parkinson's disease，PD）是一种常见的神经退行性疾病，病因不明。目前还没有治愈或经证实的策略来减缓疾病的进展。虽然在许多脑区存在病理学迹象，但PD的核心症状可归因于黑质延髓部多巴胺能神经元的选择性变性。这些神经元的脆弱性的一个潜在线索是随着年龄的增长对L型Ca2+通道的依赖性越来越大，L型Ca2+通道具有成孔Cav1.3亚基以支持自主活动。这种依赖可能会对线粒体ATP产生持续的压力，产生氧化磷酸化，加速细胞衰老和死亡。伊拉地平，这些通道的二氢吡啶阻断剂，全身给药，迫使啮齿动物多巴胺能神经元恢复到一个少年，L型钙离子通道的独立机制，产生自主活动。这种“返老还童”赋予保护免受毒素，产生实验性帕金森病，指出一个潜在的神经保护策略PD。他们在高血压治疗中数十年的安全使用记录使得二氢吡啶类药物作为PD的治疗工具特别有吸引力。(C)2010年运动障碍协会
Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. There is no cure or proven strategy for slowing the progression of the disease. Although there are signs of pathology in many brain regions, the core symptoms of PD are attributable to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. A potential clue to the vulnerability of these neurons is an increasing reliance with age upon L-type Ca2+ channels with a pore-forming Cav1.3 subunit to support autonomous activity. This reliance could pose a sustained stress on mitochondrial ATP generating oxidative phosphorylation, accelerating cellular aging and death. Systemic administration of isradipine, a dihydropyridine blocker of these channels, forces dopaminergic neurons in rodents to revert to a juvenile, L-type Ca2+ channel independent mechanism to generate autonomous activity. This "rejuvenation" confers protection against toxins that produce experimental Parkinsonism, pointing to a potential neuroprotective strategy for PD. Their decades-long track record of safe use in the treatment of hypertension makes dihydropyridines particularly attractive as a therapeutic tool in PD. (C) 2010 Movement Disorder Society