Transforming growth factor-beta signaling in motor neuron diseases.
Transforming growth factor-beta signaling in motor neuron diseases.
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DOI：
10.2174/156652411794474356
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发表时间：
2011-02-01
影响因子：
2.5
通讯作者：
Sobue, G
中科院分区：
文献类型：
--
作者：
Katsuno, M;Adachi, H;Sobue, G
转化生长因子（tgf - β）是一种多效性细胞因子，调节多种细胞反应，如增殖、分化、迁移和凋亡。tgf - β 1、β 2和β 3亚型在神经元和神经胶质细胞中表达，它们的受体在整个中枢神经系统中表达。一些证据表明，tgf - β信号保护神经元免受谷氨酸介导的兴奋性毒性，这是各种神经退行性疾病（如肌萎缩性侧索硬化症（ALS））发病机制的假定机制。最近的研究表明，tgf - β - smad2 /3通路在ALS小鼠模型中恢复运动功能，并且由于其受体转录失调而导致的tgf - β信号的破坏与多聚谷氨酰胺诱导的脊髓和球性肌萎缩的运动神经元损伤有关。此外，tgf - β - smad2 /3通路调节神经胶质细胞的功能，尽管这种调节在神经退行性疾病中的意义尚不明确。相反，肌生长抑制素作为tgf - β超家族的一员，作为神经肌肉疾病的潜在治疗靶点而受到关注，因为该因子的遗传缺失会导致肌肉体积增加。BMP是tgf - β超家族的一员，其信号转导调节神经肌肉连接处的功能和生长，而在遗传性痉挛性截瘫的动物模型中已经报道了这种信号传导的中断。这些发现支持了tgf - β信号通路的破坏是运动神经元疾病发病机制中一个重要的分子事件的假设，并且这种信号通路的修改代表了针对这些破坏性疾病的一种新的治疗策略。
Transforming growth factor beta (TGF-beta), a pleiotropic cytokine, regulates a diverse range of cellular responses, such as proliferation, differentiation, migration, and apoptosis. The TGF-beta1, -beta2, and -beta3 isoforms are expressed by neurons and glial cells, and their receptors are expressed throughout the central nervous system. Several lines of evidence demonstrate that TGF-beta signaling protects neurons from glutamate-mediated excitotoxicity, a putative mechanism underlying the pathogenesis of various neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). Recent studies indicate that the TGF-beta-Smad2/3 pathway restores motor function in a mouse model of ALS, and that disruption of TGF-beta signaling due to the transcriptional dysregulation of its receptor is associated with polyglutamine-induced motor neuron damage in spinal and bulbar muscular atrophy. Moreover, the TGF-beta-Smad2/3 pathway regulates the function of glial cells, although the implication of this regulation in neurodegeneration remains elusive. Conversely, myostatin, a member of the TGF-beta superfamily, has gained attention as a potential therapeutic target for neuromuscular disorders because genetic deletion of this factor results in increased muscle volume. Signal transduction by BMP, a member of the TGF-beta super family, regulates the function and growth of the neuromuscular junction, while the disruption of this signaling has been reported in animal models of hereditary spastic paraplegia. These findings support the hypothesis that the disruption of TGF-beta signaling is an important molecular event in the pathogenesis of motor neuron diseases, and that the modification of this signaling pathway represents a new therapeutic strategy against these devastating disorders.