Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis.
Animals
Case-Control Studies
Cholesterol
/ biosynthesis
Cuprizone
Encephalomyelitis, Autoimmune, Experimental
/ metabolism
Estrogen Receptor beta
/ metabolism
Female
Gene Expression
Homeostasis
Humans
Mice, Inbred C57BL
Middle Aged
Multiple Sclerosis
/ metabolism
Oligodendroglia
/ metabolism
Remyelination
Sequence Analysis, RNA
MS animal models
cholesterol
multiple sclerosis
oligodendrocytes
remyelination
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
14 05 2019
14 05 2019
Historique:
pubmed:
2
5
2019
medline:
31
3
2020
entrez:
2
5
2019
Statut:
ppublish
Résumé
Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain during health, and regional differences in the transcriptome may occur for each cell type during neurodegeneration. Multiple sclerosis (MS) is multifocal, and regional differences in the astrocyte transcriptome occur in experimental autoimmune encephalomyelitis (EAE), an MS model. MS and EAE are characterized by inflammation, demyelination, and axonal damage, with minimal remyelination. Here, RNA-sequencing analysis of MS tissues from six brain regions suggested a focus on oligodendrocyte lineage cells (OLCs) in corpus callosum. Olig1-RiboTag mice were used to determine the translatome of OLCs in vivo in corpus callosum during the remyelination phase of a chronic cuprizone model with axonal damage. Cholesterol-synthesis gene pathways dominated as the top up-regulated pathways in OLCs during remyelination. In EAE, remyelination was induced with estrogen receptor-β (ERβ) ligand treatment, and up-regulation of cholesterol-synthesis gene expression was again observed in OLCs. ERβ-ligand treatment in the cuprizone model further increased cholesterol synthesis gene expression and enhanced remyelination. Conditional KOs of ERβ in OLCs demonstrated that increased cholesterol-synthesis gene expression in OLCs was mediated by direct effects in both models. To address this direct effect, ChIP assays showed binding of ERβ to the putative estrogen-response element of a key cholesterol-synthesis gene (Fdps). As fetal OLCs are exposed in utero to high levels of estrogens in maternal blood, we discuss how remyelinating properties of estrogen treatment in adults during injury may recapitulate normal developmental myelination through targeting cholesterol homeostasis in OLCs.
Identifiants
pubmed: 31040210
pii: 1821306116
doi: 10.1073/pnas.1821306116
pmc: PMC6525478
doi:
Substances chimiques
Estrogen Receptor beta
0
Cuprizone
5N16U7E0AO
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
10130-10139Subventions
Organisme : NINDS NIH HHS
ID : R01 NS096748
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS109670
Pays : United States
Informations de copyright
Copyright © 2019 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
Références
Development. 2000 Oct;127(19):4277-91
pubmed: 10976058
Science. 2001 Nov 9;294(5545):1354-7
pubmed: 11701931
N Engl J Med. 2002 Jan 17;346(3):165-73
pubmed: 11796850
Cell. 2002 Apr 5;109(1):75-86
pubmed: 11955448
Mol Endocrinol. 2004 Jun;18(6):1411-27
pubmed: 15001666
Lancet. 2004 May 15;363(9421):1607-8
pubmed: 15145635
Nat Neurosci. 2005 Apr;8(4):468-75
pubmed: 15793579
Nat Neurosci. 2005 Jun;8(6):745-51
pubmed: 15895088
Glia. 2005 Nov 1;52(2):127-43
pubmed: 15920731
Nat Med. 2005 Sep;11(9):966-72
pubmed: 16086023
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14813-8
pubmed: 17785421
Neurology. 2008 Oct 28;71(18):1390-5
pubmed: 18525027
Glia. 2009 Mar;57(4):402-13
pubmed: 18814266
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13939-44
pubmed: 19666516
Exp Neurol. 2010 Sep;225(1):18-23
pubmed: 20044992
Mult Scler. 2010 Jul;16(7):848-54
pubmed: 20488825
Brain. 2010 Oct;133(10):2999-3016
pubmed: 20858739
Neurobiol Dis. 2012 Jan;45(1):108-14
pubmed: 21147224
Lancet Neurol. 2011 Aug;10(8):691-701
pubmed: 21742556
J Neurochem. 2011 Dec;119(5):1002-15
pubmed: 21899539
Neurology. 2012 Apr 10;78(15):1171-8
pubmed: 22459680
J Neurol. 2012 Nov;259(11):2401-13
pubmed: 22569835
PLoS Comput Biol. 2013;9(8):e1003118
pubmed: 23950696
Mult Scler. 2014 Apr;20(4):412-7
pubmed: 23959711
Nat Neurosci. 2013 Oct;16(10):1370-2
pubmed: 23995069
Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):19125-30
pubmed: 24191028
Lancet. 2014 Jun 28;383(9936):2213-21
pubmed: 24655729
Nat Med. 2014 Aug;20(8):954-960
pubmed: 24997607
J Neurosci. 2014 Sep 3;34(36):11929-47
pubmed: 25186741
Bioinformatics. 2015 Apr 1;31(7):1130-2
pubmed: 25417205
J Immunol. 2015 Jan 15;194(2):761-72
pubmed: 25505283
J Neurosci. 2015 Jan 7;35(1):4-20
pubmed: 25568099
Biochim Biophys Acta. 2015 Aug;1851(8):1083-94
pubmed: 25724171
Eur J Neurol. 2015 Aug;22(8):1176-83
pubmed: 25912468
Mult Scler. 2016 Aug;22(9):1163-73
pubmed: 26466947
Lancet Neurol. 2016 Jan;15(1):35-46
pubmed: 26621682
Mult Scler Relat Disord. 2016 Jan;5:53-65
pubmed: 26856944
Methods Mol Biol. 2016;1418:335-51
pubmed: 27008022
Nature. 2016 Apr 14;532(7598):195-200
pubmed: 27027288
BMC Res Notes. 2016 Sep 05;9(1):419
pubmed: 27592856
Elife. 2016 Sep 27;5:null
pubmed: 27671734
Nat Commun. 2017 Jan 24;8:14241
pubmed: 28117328
PLoS One. 2017 Jul 17;12(7):e0181349
pubmed: 28715462
Brain. 2018 Jan 1;141(1):132-147
pubmed: 29228214
Proc Natl Acad Sci U S A. 2018 Jan 9;115(2):E302-E309
pubmed: 29279367
Nature. 2018 Aug;560(7718):372-376
pubmed: 30046109
Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9580-E9589
pubmed: 30257941
Nature. 2019 Feb;566(7745):543-547
pubmed: 30747918
Acta Obstet Gynecol Scand Suppl. 1974;32(0):21-36
pubmed: 4527049
J Neurochem. 1993 Feb;60(2):577-87
pubmed: 7678286
Endocrinology. 1997 Mar;138(3):863-70
pubmed: 9048584