Swindell William R, Bojanowski Krzysztof, Kindy Mark S, Chau Raymond M W, Ko Dorothy
1Heritage College of Osteopathic Medicine, Ohio University, Athens, OH USA.
2Sunny BioDiscovery, Inc, Santa Paula, CA USA.
Transl Neurodegener. 2018 Dec 3;7:30. doi: 10.1186/s40035-018-0135-7. eCollection 2018.
Amyotrophic lateral sclerosis (ALS) is currently an incurable disease without highly effective pharmacological treatments. The peptide drug GM604 (GM6 or Alirinetide) was developed as a candidate ALS therapy, which has demonstrated safety and good drug-like properties with a favorable pharmacokinetic profile. GM6 is hypothesized to bolster neuron survival through the multi-target regulation of developmental pathways, but mechanisms of action are not fully understood.
This study used RNA-seq to evaluate transcriptome responses in SH-SY5Y neuroblastoma cells following GM6 treatment (6, 24 and 48 h).
We identified 2867 protein-coding genes with expression significantly altered by GM6 (FDR < 0.10). Early (6 h) responses included up-regulation of Notch and hedgehog signaling components, with increased expression of developmental genes mediating neurogenesis and axon growth. Prolonged GM6 treatment (24 and 48 h) altered the expression of genes contributing to cell adhesion and the extracellular matrix. GM6 further down-regulated the expression of genes associated with mitochondria, inflammatory responses, mRNA processing and chromatin organization. GM6-increased genes were located near GC-rich motifs interacting with C2H2 zinc finger transcription factors, whereas GM6-decreased genes were located near AT-rich motifs associated with helix-turn-helix homeodomain factors. Such motifs interacted with a diverse network of transcription factors encoded by GM6-regulated genes (, , , ). We identified 77 ALS-associated genes with expression significantly altered by GM6 treatment (FDR < 0.10), which were known to function in neurogenesis, axon guidance and the intrinsic apoptosis pathway.
Our findings support the hypothesis that GM6 acts through developmental-stage pathways to influence neuron survival. Gene expression responses were consistent with neurotrophic effects, ECM modulation, and activation of the Notch and hedgehog neurodevelopmental pathways. This multifaceted mechanism of action is unique among existing ALS drug candidates and may be applicable to multiple neurodegenerative diseases.
肌萎缩侧索硬化症（ALS）目前是一种无法治愈的疾病，尚无高效的药物治疗方法。肽类药物GM604（GM6或Alirinetide）被开发作为ALS治疗的候选药物，已证明其安全性良好，具有类药物特性及良好的药代动力学特征。GM6被推测可通过对发育途径的多靶点调节来增强神经元存活，但作用机制尚未完全明确。
本研究采用RNA测序技术评估GM6处理（6、24和48小时）后SH-SY5Y神经母细胞瘤细胞中的转录组反应。
我们鉴定出2867个蛋白质编码基因，其表达受到GM6的显著改变（错误发现率<0.10）。早期（6小时）反应包括Notch和刺猬信号通路成分的上调，介导神经发生和轴突生长的发育基因表达增加。GM6的长期处理（24和48小时）改变了参与细胞粘附和细胞外基质的基因表达。GM6进一步下调了与线粒体、炎症反应、mRNA加工和染色质组织相关的基因表达。GM6上调的基因位于与C2H2锌指转录因子相互作用的富含GC的基序附近，而GM6下调的基因位于与螺旋-转角-螺旋同源结构域因子相关的富含AT的基序附近。这些基序与GM6调节基因编码的多种转录因子网络相互作用（，，，）。我们鉴定出77个与ALS相关的基因，其表达受到GM6处理的显著改变（错误发现率<0.10），已知这些基因在神经发生、轴突导向和内在凋亡途径中发挥作用。
我们的研究结果支持以下假设，即GM6通过发育阶段途径发挥作用以影响神经元存活。基因表达反应与神经营养作用、细胞外基质调节以及Notch和刺猬神经发育途径的激活一致。这种多方面的作用机制在现有的ALS候选药物中是独特的，可能适用于多种神经退行性疾病。
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