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

Autor:	Germeys C; 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., Vandoorne T; 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., Davie K; VIB-KU Leuven, Center for Brain & Disease Research Technologies, Single Cell Bioinformatics Unit, 3000 Leuven, Belgium., Poovathingal S; 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., Heeren K; 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., Vermeire W; 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., Nami F; KU Leuven - University of Leuven, Department of Development and Regeneration, Stem Cell Institute Leuven (SCIL), 3000 Leuven, Belgium., Moisse M; 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., Quaegebeur A; University of Cambridge, Department of Clinical Neurosciences, CB2 2PY Cambridge, UK; Cambridge University Hospitals, Department of Histopathology, CB2 0QQ Cambridge, UK., Sierksma A; 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., Rué L; 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., Sicart A; 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., Eykens C; 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., De Cock L; 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., De Strooper B; 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., Carmeliet P; 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., Van Damme P; 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., De Bock K; ETH Zürich, Department of Health Sciences and Technology, 8092 Zürich, Switzerland., Van Den Bosch L; 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. Electronic address: ludo.vandenbosch@kuleuven.be.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Sep 24; Vol. 43 (9), pp. 114719. Date of Electronic Publication: 2024 Sep 09.
DOI:	10.1016/j.celrep.2024.114719
Abstrakt:	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. Competing Interests: Declaration of interests T.V. is an employee of Bristol-Myers Squibb (Princeton, USA). B.D.S. has been a consultant for Eli Lilly and Company (Indianapolis, USA), Biogen (Cambridge, USA), Janssen Pharmaceutica (Beerse, Belgium), AbbVie, Inc. (North Chicago, USA), and others and is now a consultant for Eisai (Nutley, USA), Remynd (Leuven, Belgium), and Muna Therapeutics (Copenhagen, Denmark). B.D.S. is a scientific founder and stockholder of Muna Therapeutics. P.V.D. has served on advisory boards for Biogen, CSL Behring (King of Prussia, USA), Alexion Pharmaceuticals (Boston, USA), Ferrer (Barcelona, Spain), QurAlis (Cambridge, UK), Cytokinetics (South San Francisco, USA), Argenx (Boston, USA), UCB (Brussels, Belgium), Muna Therapeutics, Alector (South San Francisco, USA), Augustine Therapeutics (Leuven, Belgium), VectorY (Amsterdam, the Netherlands), Zambon (Bresso, Italy), and Amylyx (Cambridge, UK) (paid to institution). P.V.D. has received speaker fees from Biogen and Amylyx (paid to institution). P.V.D. has participated as an investigator in clinical trials on ALS sponsored by Biogen, Cytokinetics, Ferrer, Amylyx, Wave Life Sciences (Cambridge, UK), Corcept Therapeutics (Menlo Park, USA), Transposon Therapeutics (Westport, USA), Sanofi (Paris, France), AB Science (Paris, France), IONIS Pharmaceuticals (Carlsbad, USA), Apellis Pharmaceuticals (Waltham, USA), Alexion Pharmaceuticals, Orphazyme (Copenhagen, Denmark), Orion Pharma (Espoo, Finland), and AL-S Pharma (Schlieren, Switzerland). P.V.D. is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders (from CSL Behring, paid to institution). L.V.D.B. is head of the scientific advisory board of Augustine Therapeutics and is part of the investment advisory board of Droia Ventures (Meise, Belgium). L.V.D.B. and B.D.S. are scientific founders of Augustine Therapeutics. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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