Abstract
Impaired myelin repair, or remyelination, is a hallmark of progressive multiple sclerosis (MS) that drives brain degeneration and enduring neurological disabilities. Microglia crucially support remyelination through myelin phagocytosis and lipid metabolism. However, in chronic demyelinated MS lesions, microglia lose their reparative function by acquiring a foamy dysfunctional phenotype characterized by accumulation of lipid droplets due to impaired cholesterol processing of myelin debris. Here, we show a positive correlation between dysregulation of neuregulin-1 and impaired oligodendrocyte remyelination in mice with chronic demyelination. Therapeutic restoration of neuregulin-1 fosters myelin regeneration through microglia-dependent mechanisms. We demonstrate that Nrg-1 signaling supports microglia integrity and function in chronic demyelinated lesions by exploiting their capacity for the clearance of myelin debris and cholesterol recycling, biosynthesis and efflux. These findings signify the promise of neuregulin-1 as an endogenous target to facilitate microglia mediated-repair in progressive MS in which there is an unmet need for new treatments.
Similar content being viewed by others
Acknowledgements
This project was funded by operating grants held by S. K-A from the Multiple Sclerosis Canada Discovery Grant (EGID3742 and 1241879), and the Canadian Institute of Health Research (PJT-191850). S.M.Z was supported by a studentship from Multiple Sclerosis Canada and the University of Manitoba Graduate Fellowship and the Hillary Kaufman Memorial Funds in Multiple Sclerosis from the University of Manitoba. E.J. was supported by a Fellowship from the Canadian Stem Cell Network and Multiple Sclerosis Canada. S.M.H. was supported by a Doctoral Studentship Grant from the Wings for Life Foundation and the Hillary Kaufman Memorial Funds in Multiple Sclerosis from the University of Manitoba. G.M. was supported by the BSc Med Program at the Rady Faculty of Health Sciences, the University of Manitoba. The authors would like to acknowledge Ms. Maria Astrid Bravo Jimenez for her assistance with animal care and some cell culture. Electron microscopy was performed by Histology Service Lab in the Department of Human Anatomy and Cell Science, University of Manitoba. Service provider for library preparation and RNA sequencing was Genome Quebec, Montreal, QC, Canada. Schematic figures were prepared with the help of items from BioRender.com online tool.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
S.K-A and H.K. are inventors on a patent entitled “USE OF NRG-1β1 FOR DETECTION AND/OR TREATMENT OF MULTIPLE SCLEROSIS” that is filed through three applications: A) Published PCT Application WO2022/056619 (completed), B) Published US Patent Application US2024/0009274, published January 11, 2024 (pending), C) Canadian Patent Application 3,191,086, date of national phase entry—February 27, 2023 (pending)—US Patent App. 18/043,199, 2024). This patent is related to the potential use of Nrg-1β1 as a treatment for multiple sclerosis. S.K-A is also an inventor on a provisional patent application titled “the NRG-1 CONDITIONAL KNOCKOUT MOUSE”, US Provisional Patent Application Serial Number 63/802,795, filed May 9, 2025 (pending). This provisional patent application is related to the Nrg-1 conditional knockout mouse model that is used in this article. The relevant interests regarding these two patent applications are managed by the University of Manitoba. All other authors declare no competing interests related to this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Ziaee, S.M., Nemati, S., Kataria, H. et al. Neuregulin-1 facilitates myelin regeneration through microglia-mediated mechanisms in a mouse model of chronic demyelination. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72639-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-72639-7
