Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons.
Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons.
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DOI：
10.1371/journal.pone.0005390
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Loeffler JP
中科院分区：
文献类型：
--
作者：
Dupuis L;Gonzalez de Aguilar JL;Echaniz-Laguna A;Eschbach J;Rene F;Oudart H;Halter B;Huze C;Schaeffer L;Bouillaud F;Loeffler JP
肌萎缩性侧索硬化症（ALS）是最常见的成人发病运动神经元疾病，与与肌肉线粒体能量代谢缺陷相关的高代谢有关，如ATP耗竭和氧消耗增加。肌萎缩侧索硬化症时，肌肉能量代谢异常是否与神经肌肉接头（NMJ）的破坏和随后的运动神经元变性有因果关系，目前尚不清楚。我们研究了肌肉过度表达解偶联蛋白1（UCP1）的转基因小鼠，一种有效的线粒体解偶联剂，作为肌肉限制性高代谢的模型。这些动物表现出年龄依赖性的NMJ恶化，与去神经支配的进行性体征和轻度迟发性运动神经元病理学相关。坐骨神经损伤后，NMJ再生和功能恢复严重延迟，肌肉线粒体解偶联加重了ALS动物模型的病理学。这些发现提供了肌肉限制性线粒体缺陷足以产生运动神经元变性的原则证据，并表明针对肌肉代谢的治疗策略可能证明对运动神经元疾病有用。
Amyotrophic lateral sclerosis (ALS), the most frequent adult onset motor neuron disease, is associated with hypermetabolism linked to defects in muscle mitochondrial energy metabolism such as ATP depletion and increased oxygen consumption. It remains unknown whether muscle abnormalities in energy metabolism are causally involved in the destruction of neuromuscular junction (NMJ) and subsequent motor neuron degeneration during ALS. We studied transgenic mice with muscular overexpression of uncoupling protein 1 (UCP1), a potent mitochondrial uncoupler, as a model of muscle restricted hypermetabolism. These animals displayed age-dependent deterioration of the NMJ that correlated with progressive signs of denervation and a mild late-onset motor neuron pathology. NMJ regeneration and functional recovery were profoundly delayed following injury of the sciatic nerve and muscle mitochondrial uncoupling exacerbated the pathology of an ALS animal model. These findings provide the proof of principle that a muscle restricted mitochondrial defect is sufficient to generate motor neuron degeneration and suggest that therapeutic strategies targeted at muscle metabolism might prove useful for motor neuron diseases.
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影响因子：
6.5
作者：
Fergani, Anissa;Oudart, Hugues;Loeffler, Jean-Philippe
通讯作者：
Loeffler, Jean-Philippe
影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
影响因子：
4.8
作者：
Couplan, E;Gelly, C;Bouillaud, F
通讯作者：
Bouillaud, F
DOI：
10.1073/pnas.0402026101
发表时间：
2004-07-27
影响因子：
11.1
作者：
Dupuis, L;Oudart, H;Loeffler, JP
通讯作者：
Loeffler, JP
DOI：
10.1073/pnas.0609411103
发表时间：
2006-12-19
影响因子：
11.1
作者：
Miller, Timothy M.;Kim, Soo H.;Kaspar, Brian K.
通讯作者：
Kaspar, Brian K.