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Nature:钙通道在帕金森氏综合症发病过程中的作用

2010/12/02 来源:Nature 中文
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导读
帕金森氏综合症的特征是,“黑质致密部 ”(substantia nigra pars compacta)中多巴胺能神经元的丢失。线粒体压力被认为引起这种丢失,但为什么是在这些细胞中而不是在其他细胞中过去却不清楚。现在Guzman等人报告,氧化物压力是由这些细胞的正常步调激发的,从

帕金森氏综合症的特征是,“黑质致密部 ”(substantia nigra pars compacta)中多巴胺能神经元的丢失。线粒体压力被认为引起这种丢失,但为什么是在这些细胞中而不是在其他细胞中过去却不清楚。现在Guzman等人报告,氧化物压力是由这些细胞的正常步调激发的,从而解释了它们的脆弱性。DJ-1(一个与帕金森氏综合症的早期发病相关的基因)的剔除会降低对这种压力的防护。步调的决定涉及L-型钙通道,用“钙通道阻断剂” (CCB) 二氢吡啶处理易感的黑质细胞,可以降低线粒体氧化压力。已经在临床上用来治疗心率不齐等状况的CCB也许代表着针对帕金森氏综合症的一种新颖的神经保护策略。


推荐原文出处:

Nature doi:10.1038/nature09536

Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1

Jaime N. Guzman1, Javier Sanchez-Padilla1, David Wokosin1, Jyothisri Kondapalli2, Ema Ilijic1, Paul T. Schumacker2 " D. James Surmeier1

1.Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA

2.Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA

Top of pageAbstractParkinson’s disease is a pervasive, ageing-related neurodegenerative disease the cardinal motor symptoms of which reflect the loss of a small group of neurons, the dopaminergic neurons in the substantia nigra pars compacta1 (SNc). Mitochondrial oxidant stress is widely viewed as being responsible for this loss2, but why these particular neurons should be stressed is a mystery. Here we show, using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, that the engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable SNc dopaminergic neurons. The oxidant stress engaged defences that induced transient, mild mitochondrial depolarization or uncoupling. The mild uncoupling was not affected by deletion of cyclophilin D, which is a component of the permeability transition pore, but was attenuated by genipin and purine nucleotides, which are antagonists of cloned uncoupling proteins. Knocking out DJ-1 (also known as PARK7 in humans and Park7 in mice), which is a gene associated with an early-onset form of Parkinson’s disease, downregulated the expression of two uncoupling proteins (UCP4 (SLC25A27) and UCP5 (SLC25A14)), compromised calcium-induced uncoupling and increased oxidation of matrix proteins specifically in SNc dopaminergic neurons. Because drugs approved for human use can antagonize calcium entry through L-type channels, these results point to a novel neuroprotective strategy for both idiopathic and familial forms of Parkinson’s disease.

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