Gene expressions specifically detected in motor neurons (Dynactin 1, early growth response 3, acetyl-CoA transporter, death receptor 5, and cyclin C) differentially correlate to Pathologic markers in sporadic amyotrophic lateral sclerosis
Gene expressions specifically detected in motor neurons (Dynactin 1, early growth response 3, acetyl-CoA transporter, death receptor 5, and cyclin C) differentially correlate to Pathologic markers in sporadic amyotrophic lateral sclerosis
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DOI：
10.1097/nen.0b013e318093ece3
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发表时间：
2007-07-01
影响因子：
3.2
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Jiang, Yue-Mei;Yamamoto, Masahiko;Sobue, Gen
在差异基因表达谱中，我们先前表明，dynactin 1（DCTN 1），早期生长反应3（EGR 3），乙酰辅酶A转运蛋白（ACATN），死亡受体5（DR 5）和细胞周期蛋白C（CCNC）在散发性肌萎缩侧索硬化症（ALS）的运动神经元中显著上调或下调。在本研究中，我们研究了这些基因的表达水平和运动神经元变性的病理标志物水平（即磷酸化神经丝H [pNF-H]和泛素化蛋白质的细胞质积累）之间的相关性，以及20例散发性ALS患者尸检中残留运动神经元的数量。DCTN 1和EGR 3广泛下调，基因表达的变化与残留运动神经元的数量相关。特别是，在pNF-H积累之前，DCTN 1在大多数残留运动神经元中显著下调，即使在运动神经元群体保存良好的情况下也是如此。ACATN、DR 5和CCNC在残余运动神经元亚群中上调，并且它们的表达水平与pNF-H积累水平和残余运动神经元的数量密切相关。DCTN 1、EGR 3、ACATN和DR 5的表达在泛素化蛋白积累之前均发生显著改变。DCTN 1下调似乎是神经变性标志物出现之前的早期事件，而DR 5和CCNC上调是与病理标志物相关的相对较晚的现象，并导致神经元死亡。在散发性ALS中运动神经元特异性基因表达变化的序列可以是开发神经变性的适当治疗策略的有益信息。
In a differential gene expression profile, we showed previously that dynactin 1 (DCTN1), early growth response 3 (EGR3), acetylCoA transporter (ACATN), death receptor 5 (DR5), and cyclin C (CCNC) were prominently up- or downregulated in motor neurons of sporadic amyotrophic lateral sclerosis (ALS). In the present study, we examined the correlation between the expression levels of these genes and the levels of pathologic markers for motor neuron degeneration (i.e. cytoplasmic accumulation of phosphorylated neurofilament H [pNF-H] and ubiquitylated protein) and the numbers of residual motor neurons in 20 autopsies of patients with sporadic ALS. DCTN1 and EGR3 were widely downregulated, and the changes in gene expression were correlated to the number of residual motor neurons. In particular, DCTN1 was markedly downregulated in most residual motor neurons before the accumulation of pNF-H, even in cases with well-preserved motor neuron populations. ACATN, DR5, and CCNC were upregulated in subpopulations of residual motor neurons, and their expression levels were well correlated with the levels of pNF-H accumulation and the number of residual motor neurons. The expressions of DCTN1, EGR3, ACATN, and DR5 were all markedly altered before ubiquitylated protein accumulation. DCTN1 downregulation appears to be an early event before the appearance of neurodegeneration markers, whereas upregulations of DR5 and CCNC are relatively later phenomena associated with pathologic markers and leading to neuronal death. The sequence of motor neuronspecific gene expression changes in sporadic ALS can be beneficial information in developing appropriate therapeutic strategies for neurodegeneration.