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

Stefan A. Berghoff, Lena Spieth, Ting Sun, Leon Hosang, Constanze Depp, Andrew O. Sasmita, Martina H. Vasileva, Patricia Scholz, Yu Zhao, Dilja Krueger-Burg, Sven Wichert, Euan R. Brown, Kyriakos Michail, Klaus-Armin Nave, Stefan Bonn, Francesca Odoardi, Moritz Rossner, Till Ischebeck, Julia M. Edgar, Gesine Saher

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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.
Original languageEnglish
Article number109889
JournalCell Reports
Volume37
Issue number4
DOIs
Publication statusPublished - 26 Oct 2021

Keywords

  • EAE
  • OPC
  • cholesterol
  • cuprizone
  • demyelination
  • knockout
  • multiple sclerosis
  • myelin
  • neuron
  • oligodendrocyte

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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