Deletion of lrrk2 causes early developmental abnormalities and age-dependent increase of monoamine catabolism in the zebrafish brain.
Animals
Anxiety
/ genetics
Biogenic Monoamines
/ metabolism
Brain
/ embryology
CRISPR-Cas Systems
Gene Deletion
Larva
/ metabolism
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
/ genetics
Monoamine Oxidase
/ metabolism
Smell
/ genetics
Swimming
Zebrafish
/ embryology
Zebrafish Proteins
/ genetics
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
14
01
2021
accepted:
24
08
2021
revised:
23
09
2021
pubmed:
14
9
2021
medline:
15
12
2021
entrez:
13
9
2021
Statut:
epublish
Résumé
LRRK2 gain-of-function is considered a major cause of Parkinson's disease (PD) in humans. However, pathogenicity of LRRK2 loss-of-function in animal models is controversial. Here we show that deletion of the entire zebrafish lrrk2 locus elicits a pleomorphic transient brain phenotype in maternal-zygotic mutant embryos (mzLrrk2). In contrast to lrrk2, the paralog gene lrrk1 is virtually not expressed in the brain of both wild-type and mzLrrk2 fish at different developmental stages. Notably, we found reduced catecholaminergic neurons, the main target of PD, in specific cell populations in the brains of mzLrrk2 larvae, but not adult fish. Strikingly, age-dependent accumulation of monoamine oxidase (MAO)-dependent catabolic signatures within mzLrrk2 brains revealed a previously undescribed interaction between LRRK2 and MAO biological activities. Our results highlight mzLrrk2 zebrafish as a tractable tool to study LRRK2 loss-of-function in vivo, and suggest a link between LRRK2 and MAO, potentially of relevance in the prodromic stages of PD.
Identifiants
pubmed: 34516550
doi: 10.1371/journal.pgen.1009794
pii: PGENETICS-D-21-00056
pmc: PMC8459977
doi:
Substances chimiques
Biogenic Monoamines
0
Zebrafish Proteins
0
Monoamine Oxidase
EC 1.4.3.4
LRRK2 protein, zebrafish
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009794Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
Nat Protoc. 2015 Nov;10(11):1709-27
pubmed: 26448360
Cell Death Differ. 2012 Oct;19(10):1623-33
pubmed: 22539006
J Neural Transm (Vienna). 2020 Feb;127(2):169-177
pubmed: 31807952
Biochem Soc Trans. 2012 Oct;40(5):1117-22
pubmed: 22988875
Microsc Res Tech. 2010 Oct;73(11):1019-29
pubmed: 20232465
Neuron. 2012 Sep 20;75(6):1008-21
pubmed: 22998870
Dev Biol. 2006 Jul 1;295(1):263-77
pubmed: 16682018
J Neurochem. 2009 Feb;108(3):719-31
pubmed: 19046410
PLoS One. 2011 Apr 06;6(4):e18568
pubmed: 21494637
Science. 2012 Dec 7;338(6112):1353-6
pubmed: 23138980
J Neurochem. 2014 Oct;131(2):239-50
pubmed: 24947832
PLoS One. 2013 Nov 14;8(11):e80705
pubmed: 24244710
PLoS Genet. 2010 Apr 22;6(4):e1000914
pubmed: 20421934
Mol Syst Biol. 2011 Oct 11;7:539
pubmed: 21988835
Bioinformatics. 2013 Jul 15;29(14):1840-1
pubmed: 23681123
Neurobiol Dis. 2015 May;77:49-61
pubmed: 25731749
Hum Mutat. 2016 Jun;37(6):564-9
pubmed: 26931183
Nat Neurosci. 2009 Jul;12(7):826-8
pubmed: 19503083
Cell Motil Cytoskeleton. 2006 Jul;63(7):415-22
pubmed: 16671106
Int J Dev Neurosci. 2010 Aug;28(5):391-9
pubmed: 20403420
PLoS One. 2013 May 10;8(5):e63778
pubmed: 23675505
Nature. 2015 Aug 13;524(7564):230-3
pubmed: 26168398
PLoS One. 2011;6(6):e20630
pubmed: 21698186
J Biol Chem. 2016 Oct 14;291(42):21880-21892
pubmed: 27539857
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):13904-9
pubmed: 23918387
Nat Med. 2010 Sep;16(9):998-1000
pubmed: 20729864
Biochem Biophys Res Commun. 2018 Mar 18;497(4):1104-1109
pubmed: 29499195
Hum Mol Genet. 2011 Nov 1;20(21):4209-23
pubmed: 21828077
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
Histochem Cell Biol. 2009 Oct;132(4):375-81
pubmed: 19603179
Nat Med. 2020 Jun;26(6):869-877
pubmed: 32461697
Neuroreport. 2007 Feb 12;18(3):273-5
pubmed: 17314670
Dev Dyn. 1995 Jul;203(3):253-310
pubmed: 8589427
J Neurosci Res. 2016 Aug;94(8):717-35
pubmed: 27265751
Biomed Res Int. 2016;2016:7681259
pubmed: 27872856
Mol Neurodegener. 2012 Apr 25;7:15
pubmed: 22534020
Neurobiol Dis. 2011 Mar;41(3):706-16
pubmed: 21168496
Neurotox Res. 2003;5(3):165-76
pubmed: 12835121
Hum Mol Genet. 2006 Jan 15;15(2):223-32
pubmed: 16321986
Hum Mutat. 2010 Jul;31(7):763-80
pubmed: 20506312
JAMA Neurol. 2018 Nov 1;75(11):1416-1422
pubmed: 30039155
Biochem J. 2010 Sep 15;430(3):393-404
pubmed: 20642453
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14622-7
pubmed: 19667187
Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9884-9
pubmed: 19497864
J Comp Neurol. 2006 Oct 10;498(5):593-610
pubmed: 16917825
Hum Mutat. 2012 Sep;33(9):1340-4
pubmed: 22581678
Neuroscience. 2008 Mar 18;152(2):429-36
pubmed: 18272292
Biomed Res Int. 2016;2016:7917128
pubmed: 27314038
PLoS One. 2015 Apr 01;10(4):e0118947
pubmed: 25830304
Biochem J. 2012 Aug 15;446(1):99-111
pubmed: 22612223
Front Neuroanat. 2011 Mar 29;5:21
pubmed: 21483723
Neuron. 2009 Dec 24;64(6):807-27
pubmed: 20064389
Development. 1998 Jul;125(13):2381-95
pubmed: 9609821
Glia. 2012 Feb;60(2):253-70
pubmed: 22020875
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9879-84
pubmed: 20457918
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16842-7
pubmed: 16269541
J Bone Miner Res. 2013 Sep;28(9):1962-74
pubmed: 23526378
Exp Cell Res. 2007 Oct 1;313(16):3658-70
pubmed: 17706965
J Neurosci. 2011 Jan 19;31(3):907-12
pubmed: 21248115
Methods Mol Biol. 2011;770:475-504
pubmed: 21805277
Elife. 2018 May 29;7:
pubmed: 29809138
Neurobiol Dis. 2014 Nov;71:62-73
pubmed: 25107341
Front Cell Neurosci. 2013 May 31;7:82
pubmed: 23754980
Mol Neurodegener. 2012 May 30;7:25
pubmed: 22647713
Mech Dev. 2003 Aug;120(8):919-36
pubmed: 12963112
Brain Res. 2013 Feb 25;1497:85-100
pubmed: 23270607
Biochem Biophys Res Commun. 2013 Jan 11;430(2):560-6
pubmed: 23220480
Neurogenetics. 2006 Jul;7(3):133-8
pubmed: 16633828
J Neurosci. 2012 Feb 1;32(5):1602-11
pubmed: 22302802
BMC Neurosci. 2007 Nov 28;8:102
pubmed: 18045479
Mov Disord. 2010 Dec 15;25(16):2717-23
pubmed: 20939082
Histochem Cell Biol. 2014 Dec;142(6):619-33
pubmed: 25028341
J Neurosci Res. 2020 Oct;98(10):1831-1842
pubmed: 32623786
Neurobiol Dis. 2015 Jun;78:172-95
pubmed: 25836420
Neuron. 2017 Nov 15;96(4):796-807.e6
pubmed: 29056298
Transl Neurodegener. 2015 Jan 08;4(1):1
pubmed: 25671103
J Mol Biol. 1990 Oct 5;215(3):403-10
pubmed: 2231712
Hum Mutat. 2012 Jul;33(7):1087-98
pubmed: 22415848
J Neurogenet. 2011 Dec;25(4):140-51
pubmed: 22077787
J Parkinsons Dis. 2016;6(1):109-17
pubmed: 26889637
Biochem J. 2007 Jul 15;405(2):307-17
pubmed: 17447891