Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome
Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome
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DOI：
10.1073/pnas.1006214107
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发表时间：
2010-06-15
影响因子：
11.1
通讯作者：
Palmiter, Richard D.
中科院分区：
文献类型：
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作者：
Quintana, Albert;Kruse, Shane E.;Palmiter, Richard D.
为了探索Ndufs4敲除（KO）小鼠中复合物I缺陷的致死性共济失调表型，我们选择性地在神经元和神经胶质（NesKO小鼠）中灭活Ndufs4。NesKO小鼠表现出与KO小鼠相同的症状，包括生长迟缓、运动能力丧失、呼吸异常和死亡，与7周相似。特定脑区的进行性神经元退化和神经胶质增生与疾病进展时的行为变化相对应，早期累及嗅球、小脑和前庭核。神经元，特别是在这些脑区，有异常的线粒体形态。在受影响的脑区，caspase 8的激活，而不是caspase 9，暗示了外源性凋亡途径的启动。有限的半胱天冬酶3激活和坏死细胞死亡的超微结构特征的优势表明在受影响的神经元从凋亡到坏死的转变。这些数据表明，在特定的大脑区域功能障碍的复合物I的结果进行性胶质细胞活化，促进神经元死亡，最终导致死亡。
To explore the lethal, ataxic phenotype of complex I deficiency in Ndufs4 knockout (KO) mice, we inactivated Ndufs4 selectively in neurons and glia (NesKO mice). NesKO mice manifested the same symptoms as KO mice including retarded growth, loss of motor ability, breathing abnormalities, and death by similar to 7 wk. Progressive neuronal deterioration and gliosis in specific brain areas corresponded to behavioral changes as the disease advanced, with early involvement of the olfactory bulb, cerebellum, and vestibular nuclei. Neurons, particularly in these brain regions, had aberrant mitochondrial morphology. Activation of caspase 8, but not caspase 9, in affected brain regions implicate the initiation of the extrinsic apoptotic pathway. Limited caspase 3 activation and the predominance of ultrastructural features of necrotic cell death suggest a switch from apoptosis to necrosis in affected neurons. These data suggest that dysfunctional complex I in specific brain regions results in progressive glial activation that promotes neuronal death that ultimately results in mortality.