Motor neuron mitochondrial dysfunction in spinal muscular atrophy
Motor neuron mitochondrial dysfunction in spinal muscular atrophy
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DOI：
10.1093/hmg/ddw262
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发表时间：
2016-08-15
影响因子：
3.5
通讯作者：
Ma, Yong-Chao
中科院分区：
文献类型：
--
作者：
Miller, Nimrod;Shi, Han;Ma, Yong-Chao
脊髓性肌萎缩症（SMA）是婴儿死亡的主要遗传原因，主要影响高代谢组织，包括运动神经元、骨骼肌和心脏。虽然SMA的遗传原因已被确定，但组织特异性脆弱性的潜在机制尚未得到很好的理解。为了研究这些机制，我们对SMA小鼠模型中脊髓运动神经元的转录组进行了深度测序分析，在该模型中，我们意外地发现了许多与线粒体生物能量学相关的基因的变化。重要的是，线粒体活性的功能测量显示SMA小鼠运动神经元中的基础和最大线粒体呼吸降低。使用还原氧化敏感的GFP和荧光传感器专门针对线粒体，我们发现增加的氧化应激水平和受损的线粒体膜电位受SMA影响的运动神经元。此外，SMA疾病条件下线粒体运动性受损，逆行转运减少，但对顺行转运无影响。我们还发现SMA小鼠的初级运动神经元中线粒体网络的碎片化显著增加，而线粒体密度没有变化。SMA小鼠脊髓的电子显微镜研究显示受疾病影响的运动神经元中的线粒体断裂、水肿和同心板层包涵体。有趣的是，SMA小鼠模型中的这些功能和结构缺陷发生在疾病的症状前阶段，表明在启动SMA中的作用。总之，我们的研究结果揭示了线粒体缺陷在SMA发病机制中的关键作用，并提出了改善疾病组织健康的新靶点。
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, predominantly affects high metabolic tissues including motor neurons, skeletal muscles and the heart. Although the genetic cause of SMA has been identified, mechanisms underlying tissue-specific vulnerability are not well understood. To study these mechanisms, we carried out a deep sequencing analysis of the transcriptome of spinal motor neurons in an SMA mouse model, in which we unexpectedly found changes in many genes associated with mitochondrial bioenergetics. Importantly, functional measurement of mitochondrial activities showed decreased basal and maximal mitochondrial respiration in motor neurons from SMA mice. Using a reduction-oxidation sensitive GFP and fluorescence sensors specifically targeted to mitochondria, we found increased oxidative stress level and impaired mitochondrial membrane potential in motor neurons affected by SMA. In addition, mitochondrial mobility was impaired in SMA disease conditions, with decreased retrograde transport but no effect on anterograde transport. We also found significantly increased fragmentation of the mitochondrial network in primary motor neurons from SMA mice, with no change in mitochondria density. Electron microscopy study of SMA mouse spinal cord revealed mitochondria fragmentation, edema and concentric lamellar inclusions in motor neurons affected by the disease. Intriguingly, these functional and structural deficiencies in the SMA mouse model occur during the presymptomatic stage of disease, suggesting a role in initiating SMA. Altogether, our findings reveal a critical role for mitochondrial defects in SMA pathogenesis and suggest a novel target for improving tissue health in the disease.