PMID- 31040210
OWN - NLM
STAT- MEDLINE
DCOM- 20200330
LR  - 20200411
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 116
IP  - 20
DP  - 2019 May 14
TI  - Gene expression in oligodendrocytes during remyelination reveals cholesterol 
      homeostasis as a therapeutic target in multiple sclerosis.
PG  - 10130-10139
LID - 10.1073/pnas.1821306116 [doi]
AB  - 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-beta (ERbeta) ligand treatment, and up-regulation of 
      cholesterol-synthesis gene expression was again observed in OLCs. ERbeta-ligand 
      treatment in the cuprizone model further increased cholesterol synthesis gene 
      expression and enhanced remyelination. Conditional KOs of ERbeta 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 ERbeta 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.
CI  - Copyright (c) 2019 the Author(s). Published by PNAS.
FAU - Voskuhl, Rhonda R
AU  - Voskuhl RR
AD  - Multiple Sclerosis Program, Department of Neurology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095 
      rvoskuhl@mednet.ucla.edu.
FAU - Itoh, Noriko
AU  - Itoh N
AD  - Multiple Sclerosis Program, Department of Neurology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Tassoni, Alessia
AU  - Tassoni A
AD  - Multiple Sclerosis Program, Department of Neurology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Matsukawa, Macy Akiyo
AU  - Matsukawa MA
AD  - Multiple Sclerosis Program, Department of Neurology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Ren, Emily
AU  - Ren E
AD  - Multiple Sclerosis Program, Department of Neurology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Tse, Vincent
AU  - Tse V
AD  - Multiple Sclerosis Program, Department of Neurology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Jang, Ellis
AU  - Jang E
AD  - Multiple Sclerosis Program, Department of Neurology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Suen, Timothy Takazo
AU  - Suen TT
AD  - Multiple Sclerosis Program, Department of Neurology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
FAU - Itoh, Yuichiro
AU  - Itoh Y
AD  - Multiple Sclerosis Program, Department of Neurology, David Geffen School of 
      Medicine, University of California, Los Angeles, CA 90095.
LA  - eng
GR  - R01 NS096748/NS/NINDS NIH HHS/United States
GR  - R01 NS109670/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20190430
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Estrogen Receptor beta)
RN  - 5N16U7E0AO (Cuprizone)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Case-Control Studies
MH  - Cholesterol/*biosynthesis
MH  - Cuprizone
MH  - Encephalomyelitis, Autoimmune, Experimental/*metabolism
MH  - Estrogen Receptor beta/metabolism
MH  - Female
MH  - Gene Expression
MH  - Homeostasis
MH  - Humans
MH  - Mice, Inbred C57BL
MH  - Middle Aged
MH  - Multiple Sclerosis/*metabolism
MH  - Oligodendroglia/*metabolism
MH  - *Remyelination
MH  - Sequence Analysis, RNA
PMC - PMC6525478
OTO - NOTNLM
OT  - MS animal models
OT  - cholesterol
OT  - multiple sclerosis
OT  - oligodendrocytes
OT  - remyelination
COIS- The authors declare no conflict of interest.
EDAT- 2019/05/02 06:00
MHDA- 2020/03/31 06:00
PMCR- 2019/04/30
CRDT- 2019/05/02 06:00
PHST- 2019/05/02 06:00 [pubmed]
PHST- 2020/03/31 06:00 [medline]
PHST- 2019/05/02 06:00 [entrez]
PHST- 2019/04/30 00:00 [pmc-release]
AID - 1821306116 [pii]
AID - 201821306 [pii]
AID - 10.1073/pnas.1821306116 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2019 May 14;116(20):10130-10139. doi: 
      10.1073/pnas.1821306116. Epub 2019 Apr 30.