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Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response

GSE219201 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2024/09/09 Platform GPL21103Platform GPL24247
Summary
The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating inflammatory responses and cellular metabolism. Both neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration leading to amyotrophic lateral sclerosis (ALS) and correlate with disease progression. Therefore, the aim of this study was to explore the role of EGLN2 in ALS. Using a genetic and an oligonucleotide-based approach, we showed that downregulation of EGLN2 protects motor neurons and mitigates the ALS-like phenotypes in a mouse and a zebrafish model of ALS. Single-nuclei RNA sequencing of murine spinal cord revealed that loss of EGLN2 induced an astrocyte-specific downregulation of pro-inflammatory interferon-stimulated genes. In addition, we found that genetic deletion of EGLN2 restored the disturbed interferon response in iPSC-derived astrocytes from an ALS patient, confirming the novel link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a potential novel ALS therapeutic target normalizing the astrocytic interferon-dependent inflammatory axis in vivo as well as in patient-derived cells
Published in
Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response
Germeys C, Vandoorne T, Davie K et al. · Cell reports 2024 · PMID 39255062 · doi:10.1016/j.celrep.2024.114719
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Also filed as BioProject PRJNA907390 and SRA study SRP410909. Searching any of these in the dataset finder brings you back here.

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