Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice

Berghoff, S. A. et al. (2021) Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice. Cell Reports, 37(4), 109889. (doi: 10.1016/j.celrep.2021.109889)

Abstract

Astrocyte-derived cholesterol supports brain cells under physiological conditions. However, in demyelinating lesions, astrocytes downregulate cholesterol synthesis, and the cholesterol that is essential for remyelination has to originate from other cellular sources. Here, we show that repair following acute versus chronic demyelination involves distinct processes. In particular, in chronic myelin disease, when recycling of lipids is often defective, de novo neuronal cholesterol synthesis is critical for regeneration. By gene expression profiling, genetic loss-of-function experiments, and comprehensive phenotyping, we provide evidence that neurons increase cholesterol synthesis in chronic myelin disease models and in patients with multiple sclerosis (MS). In mouse models, neuronal cholesterol facilitates remyelination specifically by triggering oligodendrocyte precursor cell proliferation. Our data contribute to the understanding of disease progression and have implications for therapeutic strategies in patients with MS.

• Item Type: Articles
• Additional Information: This work was funded by the Deutsche Forschungsgemeinschaft (SA 2014/2-1 to G.S.), the Wilhelm Sander-Stiftung (grant 2019.138.1 to G.S.), the Alzheimer Forschung Initiative (grant 19070 to G.S.), the UK MS Society (grant 127 to J.M.E.), the Adelson Medical Research Foundation (to K.A.N.), and Medical Research Scotland (PhD studentship 791-2014 to E.R.B.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Edgar, Professor Julia
• Authors: Berghoff, S. A., Spieth, L., Sun, T., Hosang, L., Depp, C., Sasmita, A. O., Vasileva, M. H., Scholz, P., Zhao, Y., Krueger-Burg, D., Wichert, S., Brown, E. R., Michail, K., Nave, K.-A., Bonn, S., Odoardi, F., Rossner, M., Ischebeck, T., Edgar, J. M., and Saher, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Cell Reports
• Publisher: Elsevier (Cell Press)
• ISSN: 2211-1247
• Published Online: 26 October 2021
• Copyright Holders: Copyright © 2021 The Author(s).
• First Published: First published in Cell Reports 37(4):109889
• Publisher Policy: Reproduced under a Creative Commons Licence