Centre for Discovery Brain Sciences, Deanery of Biomedical Sciences, The University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
Centre for Discovery Brain Sciences, Deanery of Biomedical Sciences, The University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK
Biol Open. 2020 May 4;9(5):bio050260. doi: 10.1242/bio.050260.
Understanding the molecular mechanisms that regulate secondary cell death after acute central nervous system (CNS) injury is critical for the development of effective neuroprotective drugs. Previous research has shown that neurotoxic processes including excitotoxicity, oxidative stress and neuroinflammation can cause secondary cell death. Nevertheless, clinical trials targeting these processes have been largely unsuccessful, suggesting that the signalling pathways underlying secondary cell death remain incompletely understood. Due to their suitability for live imaging and their amenability to genetic and pharmacological manipulation, larval zebrafish provide an ideal platform for studying the regulation of secondary cell death Here, we use RNA-seq gene expression profiling and compound screening to identify signalling pathways that regulate secondary cell death after acute neural injury in larval zebrafish. RNA-seq analysis of genes upregulated in cephalic macrophage-lineage cells isolated from transgenic larvae after neural injury suggested an involvement of cytokine and polyamine signalling in secondary cell death. Furthermore, screening a library of FDA approved compounds indicated roles for GABA, serotonin and dopamine signalling. Overall, our results highlight multiple signalling pathways that regulate secondary cell death , and thus provide a starting point for the development of novel neuroprotective treatments for patients with CNS injury.This article has an associated First Person interview with the two first authors of the paper.
了解调节急性中枢神经系统 (CNS) 损伤后继发细胞死亡的分子机制对于开发有效的神经保护药物至关重要。先前的研究表明，包括兴奋性毒性、氧化应激和神经炎症在内的神经毒性过程可导致继发细胞死亡。然而，针对这些过程的临床试验基本上都没有成功，这表明继发细胞死亡的信号通路仍不完全清楚。由于其适合活细胞成像以及易于进行遗传和药理学操作，幼鱼斑马鱼成为研究继发细胞死亡调节的理想平台。在这里，我们使用 RNA-seq 基因表达谱分析和化合物筛选来鉴定在幼鱼急性神经损伤后调节继发细胞死亡的信号通路。对神经损伤后从转基因幼鱼分离的头巨噬细胞系细胞中上调基因的 RNA-seq 分析表明细胞因子和多胺信号参与了继发细胞死亡。此外，对 FDA 批准化合物文库的筛选表明 GABA、血清素和多巴胺信号的作用。总的来说，我们的结果强调了多个调节继发细胞死亡的信号通路，从而为开发针对 CNS 损伤患者的新型神经保护治疗方法提供了起点。本文附有该论文两位第一作者的相关第一人称采访。
