Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy
Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy
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DOI：
10.1093/hmg/ddu416
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发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Ibo Galindo, Maximo
中科院分区：
文献类型：
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作者：
Lopez Del Amo, Victor;Seco-Cervera, Marta;Ibo Galindo, Maximo
与腓骨肌萎缩症（CMT）（一种遗传性周围神经病变）有关的基因之一是GDAP1。在这项工作中，我们表明，有一个真正的直系同源基因，这个基因在果蝇，我们已经命名为Gdap1。通过以组织特异性方式上调和下调Gdap1，我们发现改变其表达水平会导致线粒体大小、形态和分布以及神经元和肌肉变性的变化。有趣的是，肌肉变性是组织自主的，不依赖于神经支配。我们的实验基因型的代谢分析表明，氧化应激的改变不是神经肌肉变性的主要原因，但潜在的线粒体功能障碍的长期后果。我们的研究结果有助于更好地理解线粒体在CMT疾病中的作用，并为产生临床相关的疾病模型以研究线粒体动力学与周围神经退行性变之间的关系铺平了道路。
One of the genes involved in Charcot-Marie-Tooth (CMT) disease, an inherited peripheral neuropathy, is GDAP1. In this work, we show that there is a true ortholog of this gene in Drosophila, which we have named Gdap1. By up-and down-regulation of Gdap1 in a tissue-specific manner, we show that altering its levels of expression produces changes in mitochondrial size, morphology and distribution, and neuronal and muscular degeneration. Interestingly, muscular degeneration is tissue-autonomous and not dependent on innervation. Metabolic analyses of our experimental genotypes suggest that alterations in oxidative stress are not a primary cause of the neuromuscular degeneration but a long-term consequence of the underlying mitochondrial dysfunction. Our results contribute to a better understanding of the role of mitochondria in CMT disease and pave the way to generate clinically relevant disease models to study the relationship between mitochondrial dynamics and peripheral neurodegeneration.