VGLUT2 Is a Determinant of Dopamine Neuron Resilience in a Rotenone Model of Dopamine Neurodegeneration.
VGLUT2
dopamine
glutamate
neurodegeneration
rotenone
tyrosine hydroxylase
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:
02 06 2021
02 06 2021
Historique:
received:
30
10
2020
revised:
13
04
2021
accepted:
15
04
2021
pubmed:
25
4
2021
medline:
20
11
2021
entrez:
24
4
2021
Statut:
ppublish
Résumé
Parkinson's disease (PD) is characterized by progressive dopamine (DA) neuron loss in the SNc. In contrast, DA neurons in the VTA are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the NAc, where the majority of VGLUT2-expressing DA neurons project, exhibit greater resilience compared with DA terminals in the caudate/putamen. More broadly, VGLUT2-expressing terminals are protected throughout the striatum from rotenone-induced degeneration. Together, our data demonstrate that a distinct subpopulation of VGLUT2-expressing DA neurons are relatively protected from rotenone neurotoxicity. Rotenone-induced upregulation of the glutamatergic machinery in VTA and SNc neurons and their projections may be part of a broader neuroprotective mechanism. These findings offer a putative new target for neuronal resilience that can be manipulated to prevent toxicant-induced DA neurodegeneration in PD.
Identifiants
pubmed: 33893220
pii: JNEUROSCI.2770-20.2021
doi: 10.1523/JNEUROSCI.2770-20.2021
pmc: PMC8260163
doi:
Substances chimiques
Insecticides
0
Vesicular Glutamate Transport Protein 2
0
Rotenone
03L9OT429T
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
4937-4947Subventions
Organisme : NIEHS NIH HHS
ID : K99 ES029986
Pays : United States
Organisme : NIEHS NIH HHS
ID : R00 ES029986
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG068607
Pays : United States
Informations de copyright
Copyright © 2021 the authors.
Références
Eur J Neurosci. 2015 Mar;41(6):760-72
pubmed: 25572002
Nat Rev Neurosci. 2017 Jan 20;18(2):101-113
pubmed: 28104909
N Engl J Med. 2003 Apr 3;348(14):1356-64
pubmed: 12672864
J Neurosci. 2015 Dec 9;35(49):16259-71
pubmed: 26658874
Antioxid Redox Signal. 2012 May 1;16(9):920-34
pubmed: 21554057
Neurobiol Dis. 2013 Jun;54:158-68
pubmed: 23220621
Toxicol Sci. 2019 Jul 1;170(1):133-143
pubmed: 30907971
Eur J Neurosci. 2009 Nov;30(10):1849-59
pubmed: 19912331
Neurobiol Dis. 2019 May;125:146-153
pubmed: 30658149
FASEB J. 2019 Jan;33(1):400-417
pubmed: 30011230
Mov Disord. 2013 Jun;28(6):715-24
pubmed: 23589357
Lancet Neurol. 2006 Jun;5(6):525-35
pubmed: 16713924
Neuron. 2019 May 22;102(4):786-800.e5
pubmed: 31003725
Brain Res. 1992 May 29;581(2):283-91
pubmed: 1382801
Elife. 2017 Jul 13;6:
pubmed: 28703706
Redox Biol. 2019 Jun;24:101164
pubmed: 30925294
Biol Psychiatry. 2016 Jun 15;79(12):1006-15
pubmed: 26364548
J Neurosci. 2020 Oct 21;40(43):8262-8275
pubmed: 32928885
Curr Protoc Neurosci. 2019 Apr;87(1):e63
pubmed: 30791216
Rev Neurol (Paris). 2019 Dec;175(10):597-603
pubmed: 31543362
Rev Neurosci. 2008;19(4-5):227-44
pubmed: 19145985
Neurobiol Dis. 2020 Feb;134:104626
pubmed: 31618685
Neurochem Int. 2016 Oct;99:9-15
pubmed: 27210824
Neuron. 2000 Jan;25(1):239-52
pubmed: 10707987
Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):1931-6
pubmed: 26839413
Biophys J. 2004 Jun;86(6):3993-4003
pubmed: 15189895
Mol Pharmacol. 1986 Nov;30(5):486-96
pubmed: 2430169
Exp Physiol. 2010 Aug;95(8):841
pubmed: 20610775
J Neurosci. 2003 Nov 26;23(34):10756-64
pubmed: 14645467
J Neurosci. 2020 Feb 26;40(9):1975-1986
pubmed: 32005765
Neurotoxicology. 2015 Jan;46:101-16
pubmed: 25514659
Curr Protoc Cytom. 2014 Apr 01;68:12.33.1-22
pubmed: 24692056
Alzheimers Dement. 2014 Jun;10(3 Suppl):S213-25
pubmed: 24924672
Proc Natl Acad Sci U S A. 2018 Dec 4;115(49):E11532-E11541
pubmed: 30442663
Neurobiol Dis. 2018 Jul;115:101-114
pubmed: 29649621
Front Biosci (Landmark Ed). 2009 Jan 01;14:1197-218
pubmed: 19273125
Neurosci Biobehav Rev. 2010 Nov;35(2):129-50
pubmed: 20149820
Am J Physiol Cell Physiol. 2004 Oct;287(4):C817-33
pubmed: 15355853
Neurotox Res. 2003;5(3):165-76
pubmed: 12835121
J Clin Invest. 2018 Feb 1;128(2):774-788
pubmed: 29337309
Trends Mol Med. 2006 Nov;12(11):521-8
pubmed: 17027339
Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1265-70
pubmed: 9448320
Cell Death Discov. 2019 Aug 19;5:130
pubmed: 31452956
Neuroscience. 2008 Sep 22;156(1):59-70
pubmed: 18706980
J Neurochem. 2006 Nov;99(3):1011-8
pubmed: 16942593
Toxicol Appl Pharmacol. 2007 May 1;220(3):341-8
pubmed: 17395226
J Comp Neurol. 2009 Dec 20;517(6):873-91
pubmed: 19844994
J Neurosci. 2009 Jan 14;29(2):444-53
pubmed: 19144844
eNeuro. 2019 Aug 20;6(4):
pubmed: 31366590
Cell Commun Signal. 2013 May 17;11(1):34
pubmed: 23683503
Brain Res. 2018 Sep 1;1694:63-72
pubmed: 29763576
Neuron. 2017 Aug 30;95(5):1074-1088.e7
pubmed: 28823729
J Cell Biol. 2017 Apr 3;216(4):1091-1105
pubmed: 28254829
Neurochem Res. 2019 May;44(5):1079-1089
pubmed: 30715657
Neuron. 2010 Mar 11;65(5):643-56
pubmed: 20223200
Nat Neurosci. 2015 Mar;18(3):386-92
pubmed: 25664911
Cell Rep. 2014 Nov 6;9(3):930-43
pubmed: 25437550
Neurobiol Aging. 2007 Apr;28(4):568-78
pubmed: 16563567
Neurosci Lett. 2009 Oct 16;464(1):14-7
pubmed: 19682546
Folia Neuropathol. 2019;57(4):317-326
pubmed: 32337944
Bioessays. 2002 Apr;24(4):308-18
pubmed: 11948617
Exp Neurol. 2008 Jun;211(2):511-7
pubmed: 18417125
Neurochem Int. 2019 Oct;129:104482
pubmed: 31170424
Brain Res Mol Brain Res. 2004 Jan 5;120(2):91-102
pubmed: 14741398
Front Neuroanat. 2014 Dec 15;8:155
pubmed: 25565980
Neurobiol Dis. 2009 May;34(2):279-90
pubmed: 19385059
Nat Neurosci. 2018 Sep;21(9):1260-1271
pubmed: 30104732
Neurobiol Aging. 2014 May;35(5):1162-76
pubmed: 24315037
FEBS J. 2018 Oct;285(19):3657-3668
pubmed: 30028088
Neurodegeneration. 1996 Dec;5(4):313-8
pubmed: 9117542
Brain Res Mol Brain Res. 2005 Mar 24;134(1):109-18
pubmed: 15790535
J Neurosci. 2011 Jun 8;31(23):8476-90
pubmed: 21653852
Nat Neurosci. 2000 Dec;3(12):1301-6
pubmed: 11100151