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.
Authors
- Fatemeharefeh Nami (ORCID: https://orcid.org/0000-0002-8720-2152)
- Caroline Eykens (ORCID: https://orcid.org/0000-0002-9894-2586)
- Matthieu Moisse (ORCID: https://orcid.org/0000-0001-8880-9311)
- Kristofer Davie (ORCID: https://orcid.org/0000-0003-2182-1249)
- Philip Van Damme (ORCID: https://orcid.org/0000-0002-4010-2357)
- Katrien De Bock (ORCID: https://orcid.org/0000-0001-8232-4663)
- Annerieke Sierksma (ORCID: https://orcid.org/0000-0001-9233-972X)
- Bart De Strooper (ORCID: https://orcid.org/0000-0001-5455-5819)
- Wendy Vermeire
- Laura Rué (ORCID: https://orcid.org/0000-0001-5415-5153)
- Annelies Quaegebeur (ORCID: https://orcid.org/0000-0001-5357-9341)
- Peter Carmeliet (ORCID: https://orcid.org/0000-0001-7961-1821)
- Adrià Sicart (ORCID: https://orcid.org/0009-0004-6102-9381)
- Christine Germeys (ORCID: https://orcid.org/0000-0003-4586-7962)
- Suresh Poovathingal (ORCID: https://orcid.org/0000-0002-3236-2255)
- Tijs Vandoorne (ORCID: https://orcid.org/0000-0003-2431-7785)
- Ludo Van Den Bosch (ORCID: https://orcid.org/0000-0003-0104-4067)
- Kara Heeren
- Lenja De Cock
Institutions
- Allen Institute for Brain Science (US)
- Rega Institute for Medical Research (BE)
- University of Cambridge (GB)
- ETH Zurich (CH)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Bridge University (SS)
- VIB-KU Leuven Center for Microbiology (BE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- University College London (GB)
- KU Leuven (BE)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-09-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114719
- Citations
- 6
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 2.32
Funders
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Vlaams Instituut voor Biotechnologie
- Vlaamse regering