Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients
Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients
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DOI：
10.1002/ana.20736
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发表时间：
2006-03-01
影响因子：
11.2
通讯作者：
Trapp, BD
中科院分区：
文献类型：
--
作者：
Dutta, R;McDonough, J;Trapp, BD
目的：慢性脱髓鞘轴突变性是多发性硬化症（MS）患者不可逆神经功能障碍的主要原因。神经保护疗法的发展需要阐明神经元和轴突退化的分子机制。方法.我们报告超微结构的变化，支持钙离子介导的破坏慢性脱髓鞘轴突的MS患者。我们比较了33,000个特征基因的表达水平在死后运动皮层从6个控制和6个MS大脑匹配的年龄，性别和死后间隔。由于能量产生减少是Ca 2+介导的轴突变性的主要原因，因此我们重点关注氧化磷酸化和抑制性神经传递的变化。结果：与对照组相比，MS皮质中488个转录本减少，67个转录本增加（p < 0.05，1.5倍）。26个核编码的线粒体基因和线粒体呼吸链复合物I和III的功能活动在MS运动皮层下降。线粒体基因表达减少是神经元特有的。此外，MS皮层GABA能神经传递的突触前和突触后成分以及抑制性中间神经元突起的密度也减少。解释：我们的数据支持一种机制，即上运动神经元轴突脱髓鞘段ATP产生减少影响离子稳态，诱导Ca 2+介导的轴突变性，并有助于MS患者进行性神经功能障碍。
Objective: Degeneration of chronically demyelinated axons is a major cause of irreversible neurological disability in multiple sclerosis (MS) patients. Development of neuroprotective therapies will require elucidation of the molecular mechanisms by which neurons and axons degenerate. Methods. We report ultrastructural changes that support Ca2+-mediated destruction of chronically demyelinated axons in MS patients. We compared expression levels of 33,000 characterized genes in postmortem motor cortex from six control and six MS brains matched for age, sex, and postmortem interval. As reduced energy production is a major contributor to Ca2+-mediated axonal degeneration, we focused on changes in oxidative phosphorylation and inhibitory neurotransmission. Results: Compared with controls, 488 transcripts were decreased and 67 were increased (p < 0.05, 1.5-fold) in the MS cortex. Twenty-six nuclear-encoded mitochondrial genes and the functional activities of mitochondrial respiratory chain complexes I and III were decreased in the MS motor cortex. Reduced mitochondrial gene expression was specific for neurons. In addition, pre-synaptic and postsynaptic components of GABAergic neurotransmission and the density of inhibitory interneuron processes also were decreased in the MS cortex. Interpetation: Our data supports a mechanism whereby reduced ATP production in demyelinated segments of upper motor neuron axons impacts ion homeostasis, induces Ca2+-mediated axonal degeneration, and contributes to progressive neurological disability in MS patients.