de Oliveira Gabriela P, Maximino Jessica R, Maschietto Mariana, Zanoteli Edmar, Puga Renato D, Lima Leandro, Carraro Dirce M, Chadi Gerson
Neuroregeneration Center, Department of Neurology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 2nd Floor, Room 2119, São Paulo, 01246-903, Brazil.
Cell Mol Neurobiol. 2014 Apr;34(3):451-62. doi: 10.1007/s10571-014-0029-x. Epub 2014 Jan 18.
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.
肌萎缩侧索硬化症（ALS）是一种以运动神经元丧失为特征的神经退行性疾病。家族性ALS与铜/锌超氧化物歧化酶（SOD1）基因的显性突变密切相关。最近的证据表明，骨骼肌是ALS小鼠模型的主要靶点。Wnt/PI3K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40天和80天的症状前期，对SOD1（G93A）小鼠模型和年龄匹配的野生型对照的腓肠肌进行了Wnt/PI3K通路和EMT基因表达谱的研究，旨在研究ALS中运动神经元死亡之前的早期神经肌肉异常。使用了一个定制的包含326个Wnt/PI3K和EMT基因的cDNA微阵列平台，结果显示在40天时，有8个基因上调（Loxl2、Pik4ca、Fzd9、Cul1、Ctnnd1、Snf1lk、Prkx、Dner），9个基因下调（Pik3c2a、Ripk4、Id2、C1qdc1、Eif2ak2、Rac3、Cds1、Inppl1、Tbl1x）；在80天时，有1个基因上调（Pik3ca），5个基因下调（Cd44、Eef2k、Fzd2、Crebbp、Piki3r1）。此外，从40天和80天龄小鼠的差异表达基因构建出的蛋白质-蛋白质相互作用网络，在两个症状前期都鉴定出了Grb2和Src基因，因此它们在疾病机制中可能发挥潜在的核心作用。在80天龄的ALS小鼠中发现Grb2和Src的mRNA和蛋白质水平升高。转基因ALS小鼠在疾病症状前期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存在早期神经肌肉异常。从神经元变性的初始触发以及症状出现前肌肉为维持功能而进行的适应方面对结果进行了讨论。
