RNA-seq analyses reveal that cervical spinal cords and anterior motor neurons from amyotrophic lateral sclerosis subjects show reduced expression of mitochondrial DNA-encoded respiratory genes, and rhTFAM may correct this respiratory deficiency.
RNA-seq analyses reveal that cervical spinal cords and anterior motor neurons from amyotrophic lateral sclerosis subjects show reduced expression of mitochondrial DNA-encoded respiratory genes, and rhTFAM may correct this respiratory deficiency.
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RNA-seq 分析表明，肌萎缩侧索硬化症受试者的颈脊髓和前运动神经元表现出线粒体 DNA 编码的呼吸基因表达减少，而 rhTFAM 可能会纠正这种呼吸缺陷。
DOI：
10.1016/j.brainres.2017.05.010
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发表时间：
2017
期刊：
影响因子：
2.9
通讯作者：
Bennett,JamesP
中科院分区：
文献类型：
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作者：
Ladd,AmyC;Brohawn,DavidG;Thomas,RavindarR;Keeney,PaulaM;Berr,StuartS;Khan,ShaharyarM;Portell,FranciscoR;Shakenov,MeiramZh;Antkowiak,PatrickF;Kundu,Bijoy;Tustison,Nicholas;Bennett,JamesP
肌萎缩侧索硬化症(ALS)是一种通常致命的成人神经退行性疾病，由于上下运动神经元的功能障碍和死亡而产生虚弱和萎缩。我们使用RNA测序技术(RNA-seq)分析了所有线粒体DNA(MtDNA)编码的呼吸基因在ALS和CTL人颈脊髓(HCSC)和分离的运动神经元中的表达。通过分析重组人线粒体转录因子A(RhTFAM)诱导的人神经干细胞(HNSC)线粒体DNA基因的表达，定量分析了hNSC与其他基因的相互作用，并确定了它们的基因本体论(GO)家族。RNA-seq和定量聚合酶链式反应(QPCR)分析表明，激光捕获显微切割(LCM)分离的ALS HCSC和ALS运动神经元线粒体基因表达降低，hNSC和CTL人颈脊髓相似。静脉注射的大鼠。RhTFAM表现出脑呼吸的剂量效应增加和脊髓线粒体基因表达的增加。用重组人肿瘤坏死因子处理hNSC可增加线粒体DNA编码的呼吸基因的表达，并产生一个主要和几个次要的基因相互作用簇。基因本体论(GO)分析表明，在参与RNA和mRNA代谢的GO家族中，线粒体-核信号丰富。在死后ALS HCSC和LCM分离的运动神经元中，我们发现mtDNA呼吸基因的表达减少。在hNSC中，重组人TFAM促进mtDNA基因表达，刺激mRNA代谢，其机制尚不清楚。RhTFAM可能有助于改善ALS患者的生物能量功能。
Amyotrophic lateral sclerosis (ALS) is a generally fatal neurodegenerative disease of adults that produces weakness and atrophy due to dysfunction and death of upper and lower motor neurons. We used RNA-sequencing (RNA-seq) to analyze expression of all mitochondrial DNA (mtDNA)-encoded respiratory genes in ALS and CTL human cervical spinal cords (hCSC) and isolated motor neurons. We analyzed with RNA-seq mtDNA gene expression in human neural stem cells (hNSC) exposed to recombinant human mitochondrial transcription factor A (rhTFAM), visualized in 3-dimensions clustered gene networks activated by rhTFAM, quantitated their interactions with other genes and determined their gene ontology (GO) families.RNA-seq and quantitative PCR (qPCR) analyses showed reduced mitochondrial gene expression in ALS hCSC and ALS motor neurons isolated by laser capture microdissection (LCM), and revealed that hNSC and CTL human cervical spinal cords were similar. Rats treated with i.v. rhTFAM showed a dose-response increase in brain respiration and an increase in spinal cord mitochondrial gene expression. Treatment of hNSC with rhTFAM increased expression of mtDNA-encoded respiratory genes and produced one major and several minor clusters of gene interactions. Gene ontology (GO) analysis of rhTFAM-stimulated gene clusters revealed enrichment in GO families involved in RNA and mRNA metabolism, suggesting mitochondrial-nuclear signaling.In postmortem ALS hCSC and LCM-isolated motor neurons we found reduced expression of mtDNA respiratory genes. In hNSC’s rhTFAM increased mtDNA gene expression and stimulated mRNA metabolism by unclear mechanisms. rhTFAM may be useful in improving bioenergetic function in ALS.