Targeting EGLN2/PHD1 protects motor neurons and normalizes the astrocytic interferon response
Christine Germeys,
Tijs Vandoorne,
Kristofer Davie,
Suresh Poovathingal,
Kara Heeren,
Wendy Vermeire,
FatemehArefeh Nami,
Matthieu Moisse,
Annelies Quaegebeur,
Annerieke Sierksma,
Laura Rué,
Adrià Sicart,
Caroline Eykens,
Lenja De Cock,
Bart De Strooper,
Peter Carmeliet,
Philip Van Damme,
Katrien De Bock,
Ludo Van Den Bosch
Affiliations
Christine Germeys
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
Tijs Vandoorne
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
Kristofer Davie
VIB-KU Leuven, Center for Brain & Disease Research Technologies, Single Cell Bioinformatics Unit, 3000 Leuven, Belgium
Suresh Poovathingal
VIB-KU Leuven, Center for Brain & Disease Research Technologies, Single Cell Microfluidics & Analytics Unit, 3000 Leuven, Belgium; VIB, Center for AI & Computational Biology (VIB.AI), 3000 Leuven, Belgium
Kara Heeren
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
Wendy Vermeire
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
FatemehArefeh Nami
KU Leuven – University of Leuven, Department of Development and Regeneration, Stem Cell Institute Leuven (SCIL), 3000 Leuven, Belgium
Matthieu Moisse
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
Annelies Quaegebeur
University of Cambridge, Department of Clinical Neurosciences, CB2 2PY Cambridge, UK; Cambridge University Hospitals, Department of Histopathology, CB2 0QQ Cambridge, UK
Annerieke Sierksma
KU Leuven – University of Leuven, Department of Neurosciences, Research Group Molecular Neurobiology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory for the Research of Neurodegenerative Diseases, 3000 Leuven, Belgium
Laura Rué
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
Adrià Sicart
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
Caroline Eykens
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
Lenja De Cock
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium
Bart De Strooper
KU Leuven – University of Leuven, Department of Neurosciences, Research Group Molecular Neurobiology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory for the Research of Neurodegenerative Diseases, 3000 Leuven, Belgium; Dementia Research Institute, University College London, WC1E 6BT London, UK
Peter Carmeliet
KU Leuven – University of Leuven, Department of Oncology and Leuven Cancer Institute (LKI), Laboratory of Angiogenesis and Vascular Metabolism, 3000 Leuven, Belgium; VIB, Center for Cancer Biology, Laboratory of Angiogenesis and Vascular Metabolism, 3000 Leuven, Belgium; Khalifa University of Science and Technology, Center for Biotechnology, Abu Dhabi, United Arab Emirates
Philip Van Damme
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium; University Hospitals Leuven, Department of Neurology, 3000 Leuven, Belgium
Katrien De Bock
ETH Zürich, Department of Health Sciences and Technology, 8092 Zürich, Switzerland
Ludo Van Den Bosch
KU Leuven – University of Leuven, Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), 3000 Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, 3000 Leuven, Belgium; Corresponding author
Summary: 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.
