LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies.
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
14 10 2020
14 10 2020
Historique:
received:
14
05
2019
revised:
04
09
2019
accepted:
31
03
2020
entrez:
15
10
2020
pubmed:
16
10
2020
medline:
24
6
2021
Statut:
ppublish
Résumé
Synucleinopathies are neurodegenerative disorders characterized by abnormal α-synuclein deposition that include Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. The pathology of these conditions also includes neuronal loss and neuroinflammation. Neuron-released α-synuclein has been shown to induce neurotoxic, proinflammatory microglial responses through Toll-like receptor 2, but the molecular mechanisms involved are poorly understood. Here, we show that leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the activation of microglia by extracellular α-synuclein. Exposure to α-synuclein was found to enhance LRRK2 phosphorylation and activity in mouse primary microglia. Furthermore, genetic and pharmacological inhibition of LRRK2 markedly diminished α-synuclein-mediated microglial neurotoxicity via lowering of tumor necrosis factor-α and interleukin-6 expression in mouse cultures. We determined that LRRK2 promoted a neuroinflammatory cascade by selectively phosphorylating and inducing nuclear translocation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). NFATc2 activation was seen in patients with synucleinopathies and in a mouse model of synucleinopathy, where administration of an LRRK2 pharmacological inhibitor restored motor behavioral deficits. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies.
Identifiants
pubmed: 33055242
pii: 12/565/eaay0399
doi: 10.1126/scitranslmed.aay0399
pmc: PMC8100991
mid: NIHMS1695408
pii:
doi:
Substances chimiques
NFATC Transcription Factors
0
NFATC2 protein, human
0
Nfatc2 protein, mouse
0
Transcription Factors
0
alpha-Synuclein
0
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Lrrk2 protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Intramural NIH HHS
ID : Z99 AG999999
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Références
J Neuroinflammation. 2014 Mar 21;11:52
pubmed: 24655756
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Neuroscience. 2012 Apr 19;208:41-8
pubmed: 22342962
Mol Neurodegener. 2018 Aug 9;13(1):43
pubmed: 30092810
J Neurosci Methods. 2007 Aug 30;164(2):218-24
pubmed: 17553568
Genes Dev. 2003 Sep 15;17(18):2205-32
pubmed: 12975316
Neurobiol Aging. 2014 May;35(5):1116-24
pubmed: 24360742
Mov Disord. 2012 Aug;27(9):1104-10
pubmed: 22807207
Hum Mol Genet. 2014 Dec 15;23(24):6567-74
pubmed: 25051958
Nat Commun. 2013;4:1562
pubmed: 23463005
Neurotherapeutics. 2012 Apr;9(2):297-314
pubmed: 22350713
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D449-51
pubmed: 14681454
PLoS One. 2009;4(5):e5482
pubmed: 19424495
J Neurosci. 2012 Sep 26;32(39):13454-69
pubmed: 23015436
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13010-5
pubmed: 19651612
J Neuroinflammation. 2015 Dec 18;12:236
pubmed: 26683203
Eur J Neurosci. 2019 Feb;49(3):339-363
pubmed: 30269383
Biochem J. 2018 Jan 2;475(1):23-44
pubmed: 29127255
Mov Disord. 2011 Jan;26(1):6-17
pubmed: 21322014
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Blood. 2010 Apr 15;115(15):2989-97
pubmed: 20103781
Nat Immunol. 2001 Apr;2(4):316-24
pubmed: 11276202
Nucleic Acids Res. 2015 Jan;43(Database issue):D447-52
pubmed: 25352553
J Biol Chem. 2010 Mar 19;285(12):9262-72
pubmed: 20071342
Exp Neurobiol. 2016 Jun;25(3):113-9
pubmed: 27358579
Genome Biol. 2009;10(4):R39
pubmed: 19374773
Exp Mol Med. 2014 Apr 18;46:e91
pubmed: 24743837
Acta Neuropathol. 2011 Jun;121(6):675-93
pubmed: 21562886
Neurotoxicology. 2008 Sep;29(5):864-70
pubmed: 18471886
Nucleic Acids Res. 2014 Jan;42(Database issue):D358-63
pubmed: 24234451
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9
pubmed: 16381927
Nat Protoc. 2010 Apr;5(4):725-38
pubmed: 20360767
Acta Neuropathol. 2019 Jun;137(6):961-980
pubmed: 30927072
Cell. 2002 Apr;109 Suppl:S67-79
pubmed: 11983154
ACS Med Chem Lett. 2012 Aug 9;3(8):658-662
pubmed: 23066449
Nat Commun. 2018 Aug 27;9(1):3465
pubmed: 30150626
Front Mol Neurosci. 2014 Jun 03;7:51
pubmed: 24917786
Nat Methods. 2015 Jan;12(1):7-8
pubmed: 25549265
BMC Bioinformatics. 2008 Jan 23;9:40
pubmed: 18215316
PLoS One. 2013 May 10;8(5):e63778
pubmed: 23675505
J Neurochem. 2016 May;137(3):394-408
pubmed: 26851544
Sci Transl Med. 2018 Jun 6;10(444):
pubmed: 29875204
BMC Genomics. 2007 May 30;8:136
pubmed: 17535445
Clin Pharmacol. 2016 Oct 20;8:177-189
pubmed: 27799832
Elife. 2016 Jan 29;5:
pubmed: 26824392
J Neuroinflammation. 2012 Aug 13;9:197
pubmed: 22889165
J Neurochem. 2012 Jan;120(1):37-45
pubmed: 22004453
Biochem J. 2010 Sep 15;430(3):405-13
pubmed: 20659021
Nat Rev Immunol. 2007 Sep;7(9):690-702
pubmed: 17703229
Blood. 2012 Aug 16;120(7):1380-9
pubmed: 22611159
Nat Rev Neurol. 2014 Feb;10(2):92-8
pubmed: 24468877
Nucleic Acids Res. 2012 Jan;40(Database issue):D857-61
pubmed: 22096227
Environ Health Perspect. 2011 Jun;119(6):807-14
pubmed: 21245015
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10322-7
pubmed: 22689969
Nucleic Acids Res. 2005 Jan 1;33(Database issue):D103-7
pubmed: 15608156
Genome Res. 2008 Jul;18(7):1180-9
pubmed: 18411406
Science. 2008 Jan 25;319(5862):476-81
pubmed: 18218901
Biochem Soc Trans. 2017 Feb 8;45(1):113-122
pubmed: 28202664
Mol Neurodegener. 2009 Nov 16;4:47
pubmed: 19917131
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
F1000Res. 2018 Mar 2;7:260
pubmed: 29568499
Science. 2005 Sep 2;309(5740):1570-3
pubmed: 16141075
Biochem J. 2018 Jan 2;475(1):1-22
pubmed: 29127256
Nucleic Acids Res. 1999 Jan 1;27(1):29-34
pubmed: 9847135
Biochem Biophys Res Commun. 2008 Aug 1;372(3):423-8
pubmed: 18492487
Neurology. 1996 Nov;47(5):1113-24
pubmed: 8909416
J Neurosci. 2004 Feb 25;24(8):1888-96
pubmed: 14985429
Nucleic Acids Res. 2011 Jan;39(Database issue):D744-9
pubmed: 20947562
Exp Neurobiol. 2019 Oct 31;28(5):547-553
pubmed: 31698547
Nat Immunol. 2011 Oct 09;12(11):1063-70
pubmed: 21983832
J Neuroinflammation. 2012 Nov 29;9:261
pubmed: 23190742
J Neurochem. 2008 Oct;107(2):303-16
pubmed: 18691382
Cell Rep. 2015 Oct 27;13(4):771-782
pubmed: 26489461
J Neurosci. 2009 Nov 4;29(44):13971-80
pubmed: 19890007
PLoS One. 2012;7(4):e34693
pubmed: 22496842
Nucleic Acids Res. 2008 Jan;36(Database issue):D107-13
pubmed: 18006570
Curr Neurol Neurosci Rep. 2015 Jul;15(7):42
pubmed: 26008812
J Neurosci. 2012 Feb 1;32(5):1602-11
pubmed: 22302802
Pharmacol Ther. 2013 Jun;138(3):311-22
pubmed: 23384597
Neurobiol Dis. 2015 Jun;78:172-95
pubmed: 25836420
Prog Neurobiol. 2018 Oct;169:158-171
pubmed: 30173732
Cell. 2003 May 30;113(5):657-70
pubmed: 12787506
Acta Neuropathol. 2007 Sep;114(3):231-41
pubmed: 17576580
Behav Brain Res. 2012 Apr 1;229(1):176-84
pubmed: 22249135
Biochem J. 2016 Sep 1;473(17):2671-85
pubmed: 27474410
Nat Rev Immunol. 2010 Sep;10(9):645-56
pubmed: 20725108
Neuron Glia Biol. 2011 Feb;7(1):99-108
pubmed: 22613083
J Mol Biol. 2003 Dec 12;334(5):1009-22
pubmed: 14643663
Int J Dev Neurosci. 2008 Apr;26(2):141-5
pubmed: 18093786
Nat Struct Biol. 2003 Oct;10(10):800-6
pubmed: 12949493