@article{ab2c23dfbbc14e4a8a95b52aa3ca965e,
title = "Neuronal cholesterol synthesis is essential for repair of chronically demyelinated lesions in mice",
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.",
keywords = "EAE, OPC, cholesterol, cuprizone, demyelination, knockout, multiple sclerosis, myelin, neuron, oligodendrocyte",
author = "Berghoff, {Stefan A.} and Lena Spieth and Ting Sun and Leon Hosang and Constanze Depp and Sasmita, {Andrew O.} and Vasileva, {Martina H.} and Patricia Scholz and Yu Zhao and Dilja Krueger-Burg and Sven Wichert and Brown, {Euan R.} and Kyriakos Michail and Klaus-Armin Nave and Stefan Bonn and Francesca Odoardi and Moritz Rossner and Till Ischebeck and Edgar, {Julia M.} and Gesine Saher",
note = "Funding Information: We cordially thank Annette Fahrenholz, Annika M. Schmidke, and Tanja Freerck for technical support and Dr. Matthew Euston for supplying myelinating cell cultures. We thank Charles Stiles, John Alberta, and Said Ghandour for generous gifts of antibodies. 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.). S.A.B. and G.S. planned and designed the study. S.A.B. and L.S. were involved in all experiments. T.S. Y.Z. and S.B. performed reanalysis of human snRNA-seq datasets. L.H. and F.O. did flow cytometry. T.I. and P.S. performed lipid mass spectrometry. M.H.V. performed histology. C.D. and A.O.S. did light sheet microscopy. D.K.-B. was involved in behavior experiments. S.W. K.-A.N. and M.R. analyzed genetic myelin mutants. J.M.E. conducted myelinating cell culture experiments. K.M. and E.R.B. conducted electrophysiology experiments on myelinating cell cultures. S.A.B. and G.S. wrote and edited the manuscript. All authors approved the manuscript. The authors declare no competing interests. Funding Information: We cordially thank Annette Fahrenholz, Annika M. Schmidke, and Tanja Freerck for technical support and Dr. Matthew Euston for supplying myelinating cell cultures. We thank Charles Stiles, John Alberta, and Said Ghandour for generous gifts of antibodies. 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.). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = oct,
day = "26",
doi = "10.1016/j.celrep.2021.109889",
language = "English",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "4",
}