Early Gene Expression Changes in Skeletal Muscle from SOD1G93A Amyotrophic Lateral Sclerosis Animal Model
Early Gene Expression Changes in Skeletal Muscle from SOD1G93A Amyotrophic Lateral Sclerosis Animal Model
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DOI：
10.1007/s10571-014-0029-x
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发表时间：
2014-04-01
影响因子：
4
通讯作者：
Chadi, Gerson
中科院分区：
文献类型：
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作者：
de Oliveira, Gabriela P.;Maximino, Jessica R.;Chadi, Gerson
肌萎缩侧索硬化症（ALS）是一种以运动神经元缺失为特征的神经退行性疾病。家族性ALS与Cu/Zn超氧化物歧化酶（SOD 1）基因的显性突变密切相关。最近的证据指出骨骼肌是ALS小鼠模型的主要靶点。Wnt/PI 3 K信号通路和上皮-间质转化（EMT）在骨骼肌的维持和修复中起重要作用。在症状前40天和80天，研究了来自SOD 1（G93 A）小鼠模型和年龄配对的野生型对照的腓肠肌中Wnt/PI 3 K通路和EMT基因表达谱，旨在研究ALS中运动神经元死亡之前的早期神经肌肉异常。利用定制的包含326个Wnt/PI 3 K和EMT基因的cDNA微阵列平台，结果显示8个上调的Wnt/PI 3 K和EMT基因，（Loxl 2，Pik 4ca，Fzd 9，Cul 1，Ctnnd 1，Snf 1 lk，Prkx，Dner）和9个下调的（Pik 3c 2a、Ripk 4、Id 2、C1 qdc 1、Eif 2ak 2、Rac 3、Cds 1、Inpp 11、Tbl 1x）基因，并且在40天时也有一个上调（Pik 3ca）和五个下调（Pik 3ca）基因。（Cd 44、Eef 2 k、Fzd 2、Crebbp、Piki 3r 1）基因。此外，从40和80天龄小鼠的差异表达基因中生长的蛋白质-蛋白质相互作用网络已经在两个症状前年龄中鉴定出Grb 2和Src基因，从而在疾病机制中发挥潜在的核心作用。发现Grb 2和Src的mRNA和蛋白水平在80日龄ALS小鼠中增加。转基因ALS小鼠在疾病症状前骨骼肌中的基因表达变化进一步证明了运动神经元死亡之前的早期神经肌肉异常。从神经元变性的初始触发和肌肉适应以在症状出现之前保持功能的角度讨论了结果。
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motor neurons. Familial ALS is strongly associated to dominant mutations in the gene for Cu/Zn superoxide dismutase (SOD1). Recent evidences point to skeletal muscle as a primary target in the ALS mouse model. Wnt/PI3 K signaling pathways and epithelial-mesenchymal transition (EMT) have important roles in maintenance and repair of skeletal muscle. Wnt/PI3 K pathways and EMT gene expression profile were investigated in gastrocnemius muscle from SOD1(G93A) mouse model and age-paired wild-type control in the presymptomatic ages of 40 and 80 days aiming the early neuromuscular abnormalities that precede motor neuron death in ALS. A customized cDNA microarray platform containing 326 genes of Wnt/PI3 K and EMT was used and results revealed eight up-regulated (Loxl2, Pik4ca, Fzd9, Cul1, Ctnnd1, Snf1lk, Prkx, Dner) and nine down-regulated (Pik3c2a, Ripk4, Id2, C1qdc1, Eif2ak2, Rac3, Cds1, Inppl1, Tbl1x) genes at 40 days, and also one up-regulated (Pik3ca) and five down-regulated (Cd44, Eef2 k, Fzd2, Crebbp, Piki3r1) genes at 80 days. Also, protein-protein interaction networks grown from the differentially expressed genes of 40 and 80 days old mice have identified Grb2 and Src genes in both presymptomatic ages, thus playing a potential central role in the disease mechanisms. mRNA and protein levels for Grb2 and Src were found to be increased in 80 days old ALS mice. Gene expression changes in the skeletal muscle of transgenic ALS mice at presymptomatic periods of disease gave further evidence of early neuromuscular abnormalities that precede motor neuron death. The results were discussed in terms of initial triggering for neuronal degeneration and muscle adaptation to keep function before the onset of symptoms.