Blocking the Thrombin Receptor Promotes Repair of Demyelinated Lesions in the Adult Brain.
Animals
Astrocytes
/ drug effects
Axons
/ pathology
Brain-Derived Neurotrophic Factor
/ biosynthesis
Chelating Agents
/ toxicity
Coculture Techniques
Copper
Corpus Callosum
/ drug effects
Cuprizone
/ toxicity
Demyelinating Diseases
/ chemically induced
Gene Expression Profiling
Lysophosphatidylcholines
/ toxicity
Male
Mice
Mice, Knockout
Myelin Sheath
/ physiology
Nerve Regeneration
/ drug effects
Neural Stem Cells
/ drug effects
Oligodendroglia
/ drug effects
Receptor, PAR-1
/ antagonists & inhibitors
Rotarod Performance Test
Spinal Cord
/ drug effects
White Matter
/ drug effects
astrocyte
brain derived neurotrophic factor
myelin
oligodendrocyte progenitor cells
protease activated receptor
regeneration
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN: 1529-2401
Titre abrégé: J Neurosci
Pays: United States
ID NLM: 8102140
Informations de publication
Date de publication:
12 02 2020
12 02 2020
Historique:
received:
19
08
2019
revised:
15
12
2019
accepted:
17
12
2019
pubmed:
9
1
2020
medline:
20
8
2020
entrez:
9
1
2020
Statut:
ppublish
Résumé
Myelin loss limits neurological recovery and myelin regeneration and is critical for restoration of function. We recently discovered that global knock-out of the thrombin receptor, also known as Protease Activated Receptor 1 (PAR1), accelerates myelin development. Here we demonstrate that knocking out PAR1 also promotes myelin regeneration. Outcomes in two unique models of myelin injury and repair, that is lysolecithin or cuprizone-mediated demyelination, showed that PAR1 knock-out in male mice improves replenishment of myelinating cells and remyelinated nerve fibers and slows early axon damage. Improvements in myelin regeneration in PAR1 knock-out mice occurred in tandem with a skewing of reactive astrocyte signatures toward a prorepair phenotype. In cell culture, the promyelinating effects of PAR1 loss of function are consistent with possible direct effects on the myelinating potential of oligodendrocyte progenitor cells (OPCs), in addition to OPC-indirect effects involving enhanced astrocyte expression of promyelinating factors, such as BDNF. These findings highlight previously unrecognized roles of PAR1 in myelin regeneration, including integrated actions across the oligodendrocyte and astroglial compartments that are at least partially mechanistically linked to the powerful BDNF-TrkB neurotrophic signaling system. Altogether, findings suggest PAR1 may be a therapeutically tractable target for demyelinating disorders of the CNS.
Identifiants
pubmed: 31911460
pii: JNEUROSCI.2029-19.2019
doi: 10.1523/JNEUROSCI.2029-19.2019
pmc: PMC7044736
doi:
Substances chimiques
Bdnf protein, mouse
0
Brain-Derived Neurotrophic Factor
0
Chelating Agents
0
Lysophosphatidylcholines
0
Receptor, PAR-1
0
Cuprizone
5N16U7E0AO
Copper
789U1901C5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1483-1500Subventions
Organisme : NINDS NIH HHS
ID : R01 NS052741
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS107946
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM065841
Pays : United States
Informations de copyright
Copyright © 2020 the authors.
Références
Front Neurosci. 2018 Jul 11;12:467
pubmed: 30050403
Elife. 2016 Sep 27;5:
pubmed: 27671734
Brain. 2006 Dec;129(Pt 12):3165-72
pubmed: 16921173
J Neurosci. 2013 Mar 13;33(11):4947-57
pubmed: 23486965
Ophthalmic Physiol Opt. 2014 Sep;34(5):502-8
pubmed: 24697967
Glia. 2007 Mar;55(4):400-11
pubmed: 17186502
Neurobiol Dis. 2016 Sep;93:226-42
pubmed: 27145117
Annu Rev Med. 2017 Jan 14;68:431-443
pubmed: 27860545
Sci Rep. 2017 Mar 03;7:43606
pubmed: 28256580
Glia. 2019 Feb;67(2):291-308
pubmed: 30456797
Biol Chem. 2012 Apr;393(5):355-67
pubmed: 22505518
Alzheimers Dement. 2018 Aug;14(8):998-1004
pubmed: 29679574
J Neurochem. 2002 Feb;80(4):655-66
pubmed: 11841573
J Neurosci. 2011 Sep 14;31(37):13028-38
pubmed: 21917786
J Neurosci. 2011 Oct 5;31(40):14182-90
pubmed: 21976503
J Neurosci. 2003 Aug 20;23(20):7710-8
pubmed: 12930811
Cold Spring Harb Protoc. 2013 Sep 01;2013(9):810-4
pubmed: 24003197
Nature. 2017 Jan 26;541(7638):481-487
pubmed: 28099414
Proc Natl Acad Sci U S A. 2016 Dec 20;113(51):14829-14834
pubmed: 27930320
ASN Neuro. 2012 Oct 30;4(6):393-408
pubmed: 23025787
Brain Pathol. 2001 Jan;11(1):107-16
pubmed: 11145196
Nat Neurosci. 2013 Sep;16(9):1211-1218
pubmed: 23872599
Neuroscience. 2014 Dec 5;281:229-40
pubmed: 25261684
Curr Top Microbiol Immunol. 2008;318:133-75
pubmed: 18219817
Neurobiol Dis. 2017 Sep;105:142-155
pubmed: 28576706
J Neurosci. 2008 Jan 2;28(1):264-78
pubmed: 18171944
Brain. 2002 Jun;125(Pt 6):1283-96
pubmed: 12023317
Nature. 1979 Aug 2;280(5721):395-6
pubmed: 460414
Nature. 2019 Feb;566(7745):538-542
pubmed: 30675058
Neuron. 2014 Feb 5;81(3):588-602
pubmed: 24507193
Curr Neuropharmacol. 2019;17(2):129-141
pubmed: 28714395
JCI Insight. 2017 Apr 20;2(8):
pubmed: 28422748
Sci Rep. 2017 Apr 07;7:45780
pubmed: 28387380
Glia. 2012 Nov;60(11):1684-95
pubmed: 22836368
Neurobiol Dis. 2010 Aug;39(2):127-37
pubmed: 20347981
Stroke. 2015 Jan;46(1):221-8
pubmed: 25395417
J Neurosci. 2018 Aug 8;38(32):7088-7099
pubmed: 29976621
Int J Biochem Cell Biol. 2008;40(10):1971-8
pubmed: 18468478
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1896-E1905
pubmed: 29437957
Brain. 2013 Jan;136(Pt 1):147-67
pubmed: 23266461
Sci Rep. 2018 Jun 19;8(1):9360
pubmed: 29921916
Glia. 2017 Dec;65(12):2070-2086
pubmed: 28921694
Eur J Neurosci. 1998 Jul;10(7):2400-15
pubmed: 9749768
Nature. 2013 Oct 17;502(7471):327-332
pubmed: 24107995
Glia. 2015 May;63(5):846-59
pubmed: 25628003
Nat Med. 2018 Jul;24(7):931-938
pubmed: 29892066
J Exp Med. 2015 Apr 6;212(4):481-95
pubmed: 25779633
Elife. 2019 May 09;8:
pubmed: 31071011
Nat Neurosci. 2019 Jul;22(7):1046-1052
pubmed: 31182869
Glia. 2013 Sep;61(9):1456-70
pubmed: 23832758
Acta Neuropathol Commun. 2018 Mar 2;6(1):22
pubmed: 29499767
J Neurosci. 2014 Jun 11;34(24):8186-96
pubmed: 24920623
Biol Chem. 2018 Sep 25;399(9):1041-1052
pubmed: 29604205
J Neurochem. 2008 Nov;107(3):855-70
pubmed: 18778305
J Neurosci. 2005 Apr 27;25(17):4319-29
pubmed: 15858058
Nat Neurosci. 2005 Jun;8(6):745-51
pubmed: 15895088