PUBLICATION

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

Authors
Germeys, C., Vandoorne, T., Davie, K., Poovathingal, S., Heeren, K., Vermeire, W., Nami, F., Moisse, M., Quaegebeur, A., Sierksma, A., Rué, L., Sicart, A., Eykens, C., De Cock, L., De Strooper, B., Carmeliet, P., Van Damme, P., De Bock, K., Van Den Bosch, L.
ID
ZDB-PUB-240911-7
Date
2024
Source
Cell Reports   43: 114719114719 (Journal)
Registered Authors
Keywords
ALS, C9orf72, CP: Neuroscience, EGLN2, PHD1, SOD1, astrocyte, cGAS/STING, interferon, motor neuron, single-nucleus RNA sequencing
MeSH Terms
  • Amyotrophic Lateral Sclerosis*/drug therapy
  • Amyotrophic Lateral Sclerosis*/genetics
  • Amyotrophic Lateral Sclerosis*/metabolism
  • Amyotrophic Lateral Sclerosis*/pathology
  • Animals
  • Astrocytes*/metabolism
  • Disease Models, Animal
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors
  • Hypoxia-Inducible Factor-Proline Dioxygenases/genetics
  • Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism
  • Induced Pluripotent Stem Cells/metabolism
  • Interferons/metabolism
  • Mice
  • Motor Neurons*/metabolism
  • Zebrafish*/metabolism
PubMed
39255062 Full text @ Cell Rep.
Citation
Germeys, C., Vandoorne, T., Davie, K., Poovathingal, S., Heeren, K., Vermeire, W., Nami, F., Moisse, M., Quaegebeur, A., Sierksma, A., Rué, L., Sicart, A., Eykens, C., De Cock, L., De Strooper, B., Carmeliet, P., Van Damme, P., De Bock, K., Van Den Bosch, L. (2024) Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response. Cell Reports. 43:114719114719.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
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