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

Neuroinflammation and dysregulated energy metabolism are linked to motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The egl-9 family hypoxia-inducible factor (EGLN) enzymes, also known as prolyl hydroxylase domain (PHD) enzymes, are metabolic sensors regulating cellular inflammation and metabolism. Using an oligonucleotide-based and a genetic approach, we showed that the downregulation of Egln2 protected motor neurons and mitigated the ALS phenotype in two zebrafish models and a mouse model of ALS. Single-nucleus RNA sequencing of the murine spinal cord revealed that the loss of EGLN2 induced an astrocyte-specific downregulation of interferon-stimulated genes, mediated via the stimulator of interferon genes (STING) protein. In addition, we found that the genetic deletion of EGLN2 restored this interferon response in patient induced pluripotent stem cell (iPSC)-derived astrocytes, confirming the link between EGLN2 and astrocytic interferon signaling. In conclusion, we identified EGLN2 as a motor neuron protective target normalizing the astrocytic interferon-dependent inflammatory axis in vivo, as well as in patient-derived cells. [Display omitted] •Egln2 knockdown rescues motor axonopathy in both C9- and SOD1-ALS zebrafish•Egln2 deletion mitigates ALS phenotypes in SOD1-ALS mice and prolongs survival•EGLN2 deletion normalizes STING-induced interferon response in ALS astrocytes Germeys et al. identify EGLN2 as an ALS target that, when downregulated, protects motor neurons and mitigates the ALS phenotype in ALS zebrafish and mice. Using snRNA-seq and CRISPR-Cas9-edited patient iPSCs, they show that the downregulation of EGLN2 normalizes the STING-induced astrocytic interferon response in vivo and in patient-derived cells.