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RNA-seq analysis and compound screening highlight multiple signalling pathways regulating secondary cell death after
Chiara Herzog1, David Greenald1, Juan Larraz1
1Centre for Discovery Brain Sciences, Deanery of Biomedical Sciences, The University of Edinburgh, 49 Little France Crescent, Edinburgh EH16 4SB, UK.
Abstract:
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 in vivo 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 mpeg1+ macrophage-lineage cells isolated from mpeg1:GFP 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 in vivo, 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.
Insights
This study identifies key molecular pathways regulating secondary cell death after central nervous system (CNS) injury in zebrafish. Findings offer new targets for developing effective neuroprotective drugs to treat CNS damage.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Secondary cell death after acute central nervous system (CNS) injury is a major challenge.
- Current neuroprotective strategies targeting excitotoxicity, oxidative stress, and neuroinflammation have shown limited clinical success.
- Understanding the underlying molecular signaling pathways is crucial for developing novel treatments.
Purpose of the Study:
- To identify novel signaling pathways regulating secondary cell death in vivo.
- To explore potential therapeutic targets for neuroprotection following CNS injury.
Main Methods:
- Utilized larval zebrafish as an in vivo model for studying CNS injury.
- Employed RNA-sequencing (RNA-seq) for gene expression profiling of macrophage-lineage cells.
- Screened a library of FDA-approved compounds to identify active signaling pathways.
Main Results:
- RNA-seq revealed upregulation of cytokine and polyamine signaling pathways in response to neural injury.
- Compound screening identified GABA, serotonin, and dopamine signaling as regulators of secondary cell death.
- Highlighted multiple, previously unappreciated, signaling pathways involved in post-injury cell death.
Conclusions:
- Identified novel molecular mechanisms governing secondary cell death after acute CNS injury.
- Provides a foundation for developing innovative neuroprotective therapies.
- Demonstrates the utility of zebrafish models for in vivo drug discovery and mechanism elucidation.
