Germeys, Christine;
Vandoorne, Tijs;
Davie, Kristofer;
Poovathingal, Suresh;
Heeren, Kara;
Vermeire, Wendy;
Nami, FatemehArefeh;
... Van Den Bosch, Ludo; + view all
(2024)
Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response.
Cell Reports
, 43
(9)
, Article 114719. 10.1016/j.celrep.2024.114719.
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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.
| Type: | Article |
|---|---|
| Title: | Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.celrep.2024.114719 |
| Publisher version: | http://dx.doi.org/10.1016/j.celrep.2024.114719 |
| Language: | English |
| Additional information: | Copyright © 2024 The Author(s). Published by Elsevier Inc. 1 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | ALS; SOD1; C9orf72; EGLN2; PHD1; single-nucleus RNA sequencing; motor neuron; astrocyte; interferon; cGAS/STING |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10197877 |
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