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Edaravone activates the GDNF/RET neurotrophic signaling pathway and protects mRNA-induced motor neurons from iPS cells
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2022-01-10 , DOI: 10.1186/s13024-021-00510-y
Qian Li 1, 2 , Yi Feng 2 , Yingchao Xue 2 , Xiping Zhan 3 , Yi Fu 1 , Gege Gui 4 , Weiqiang Zhou 5 , Jean-Philippe Richard 6 , Arens Taga 6 , Pan Li 5 , Xiaobo Mao 6 , Nicholas J Maragakis 6 , Mingyao Ying 2, 6
Affiliation  

Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy. We induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy. We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H2O2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H2O2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment. This study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases.

中文翻译:

Edaravone 激活 GDNF/RET 神经营养信号通路并保护 mRNA 诱导的运动神经元免受 iPS 细胞的影响

来自人类 iPS 细胞 (iPSC) 的脊髓运动神经元 (MN) 在肌萎缩侧索硬化症 (ALS) 和其他 MN 相关神经退行性疾病的疾病建模和治疗开发中具有广泛的应用。我们需要高效的 MN 分化策略来生成 iPSC 衍生的疾病模型,以密切概括 ALS 的遗传和表型复杂性。这些模型的一个重要应用是了解 FDA 批准的 ALS 药物的分子作用机制,这些药物仅显示出有限的临床疗效。新颖的机制见解将帮助我们设计最佳的治疗策略以及预测性生物标志物,以实现更好的疗效。我们使用编码具有磷酸位点修饰的两种转录因子(Ngn2 和 Olig2)的合成 mRNA,在 4 天内诱导 iPSC 的有效 MN 分化。经过广泛表征后,这些 MN 被应用于电生理学和神经毒性测定以及转录组分析,以研究依达拉奉(FDA 批准的 ALS 药物)的神经保护作用和分子机制,以提高其临床疗效。我们从对照和 ALS iPSC 以及胚胎干细胞中生成高纯度和功能性 mRNA 诱导的 MN (miMN)。Edaravone 可减轻 H2O2 诱导的 miMN 神经毒性和电生理功能障碍,证明其具有神经保护作用,在谷氨酸诱导的 miMN 神经毒性模型中也发现了这种作用。在转录组分析的指导下,我们展示了依达拉奉在体外和体内诱导 GDNF 受体 RET 和 GDNF/RET 神经营养信号传导的先前未被认识的作用,这表明了激活这一关键神经保护信号传导的临床可转化策略。值得注意的是,依达拉奉可以替代所需的神经营养因子(BDNF 和 GDNF)以支持 miMN 的长期存活和成熟,进一步支持依达拉奉激活的信号传导的神经营养功能。此外,我们发现依达拉奉和 GDNF 联合治疗比单一治疗更有效地保护 miMN 免受 H2O2 诱导的神经毒性,这表明 ALS 治疗的潜在联合策略。这项研究提供了促进 iPSC 分化和疾病建模的方法。我们的发现将促进针对 ALS 和其他潜在神经退行性疾病的最佳基于依达拉奉的疗法的开发。
更新日期:2022-01-10
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