Reconstitution of the Human Nigro-striatal Pathway on-a-Chip Reveals OPA1-Dependent Mitochondrial Defects and Loss of Dopaminergic Synapses.
Axons
/ metabolism
Cells, Cultured
Dopaminergic Neurons
/ metabolism
GTP Phosphohydrolases
/ genetics
Humans
Induced Pluripotent Stem Cells
/ metabolism
Lab-On-A-Chip Devices
Mitochondria
/ metabolism
Mutation
/ genetics
Neostriatum
/ metabolism
Nerve Net
/ metabolism
Neurites
/ metabolism
Parkinson Disease
/ metabolism
Substantia Nigra
/ metabolism
Synapses
/ metabolism
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
24 12 2019
24 12 2019
Historique:
received:
19
03
2019
revised:
26
10
2019
accepted:
26
11
2019
entrez:
26
12
2019
pubmed:
26
12
2019
medline:
29
9
2020
Statut:
ppublish
Résumé
Stem cell-derived neurons are generally obtained in mass cultures that lack both spatial organization and any meaningful connectivity. We implement a microfluidic system for long-term culture of human neurons with patterned projections and synaptic terminals. Co-culture of human midbrain dopaminergic and striatal medium spiny neurons on the microchip establishes an orchestrated nigro-striatal circuitry with functional dopaminergic synapses. We use this platform to dissect the mitochondrial dysfunctions associated with a genetic form of Parkinson's disease (PD) with OPA1 mutations. Remarkably, we find that axons of OPA1 mutant dopaminergic neurons exhibit a significant reduction of mitochondrial mass. This defect causes a significant loss of dopaminergic synapses, which worsens in long-term cultures. Therefore, PD-associated depletion of mitochondria at synapses might precede loss of neuronal connectivity and neurodegeneration. In vitro reconstitution of human circuitries by microfluidic technology offers a powerful system to study brain networks by establishing ordered neuronal compartments and correct synapse identity.
Identifiants
pubmed: 31875567
pii: S2211-1247(19)31634-1
doi: 10.1016/j.celrep.2019.11.111
pmc: PMC6941223
pii:
doi:
Substances chimiques
GTP Phosphohydrolases
EC 3.6.1.-
OPA1 protein, human
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4646-4656.e4Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
Références
Neuron. 2010 Apr 15;66(1):57-68
pubmed: 20399729
Annu Rev Pathol. 2019 Jan 24;14:449-468
pubmed: 30355153
Mov Disord. 2017 Mar;32(3):346-363
pubmed: 28251677
Cell Rep. 2018 Feb 20;22(8):2066-2079
pubmed: 29466734
Nat Med. 2018 Oct;24(10):1579-1589
pubmed: 30127392
Cell Stem Cell. 2014 Nov 6;15(5):653-65
pubmed: 25517469
Nat Protoc. 2006;1(4):2128-36
pubmed: 17487204
Ann Neurol. 2008 Jun;63(6):794-8
pubmed: 18496845
Cell Rep. 2016 Apr 26;15(4):692-699
pubmed: 27149846
J Neurosci. 2015 Jun 17;35(24):8979-85
pubmed: 26085623
Nat Methods. 2005 Aug;2(8):599-605
pubmed: 16094385
J Neurosci. 2016 Nov 16;36(46):11573-11584
pubmed: 27852766
Front Neurosci. 2017 Dec 13;11:671
pubmed: 29326542
Development. 2015 Sep 15;142(18):3178-87
pubmed: 26395144
Curr Opin Neurobiol. 2016 Feb;36:118-27
pubmed: 26705693
Cell Rep. 2012 Jun 28;1(6):703-14
pubmed: 22813745
Cell Rep. 2018 Jan 2;22(1):110-122
pubmed: 29298414
Mol Cell Neurosci. 2014 May;60:43-52
pubmed: 24662423
Cell Stem Cell. 2016 Nov 3;19(5):573-586
pubmed: 27814479
PLoS One. 2016 Jan 29;11(1):e0148219
pubmed: 26824698
Acta Neuropathol. 2016 Apr;131(4):539-48
pubmed: 26820848
Brain. 2013 Aug;136(Pt 8):2419-31
pubmed: 23884810
Neuron. 2018 May 16;98(4):865
pubmed: 29772206
Mov Disord. 2018 Apr;33(4):592-599
pubmed: 29436751
Nat Med. 2011 Dec;17(12):1570-6
pubmed: 22146428
Cell Stem Cell. 2013 Dec 5;13(6):635-6
pubmed: 24315433
Cell Stem Cell. 2009 Dec 4;5(6):584-95
pubmed: 19951687
Stem Cell Reports. 2019 Feb 12;12(2):230-244
pubmed: 30639210
Nat Rev Drug Discov. 2017 Feb;16(2):115-130
pubmed: 27980341
Nature. 2011 Nov 06;480(7378):547-51
pubmed: 22056989
ACS Chem Biol. 2013 Sep 20;8(9):1947-54
pubmed: 23859623
Brain. 2008 Feb;131(Pt 2):352-67
pubmed: 18222991
Science. 2018 Jun 29;360(6396):
pubmed: 29853555
Neurobiol Dis. 2017 Jul;103:101-112
pubmed: 28411117
Stem Cell Reports. 2015 Dec 8;5(6):933-945
pubmed: 26610635
Development. 2015 Apr 1;142(7):1375-86
pubmed: 25804741
J Neurosci. 2014 Oct 22;34(43):14304-17
pubmed: 25339743
Annu Rev Genet. 2018 Nov 23;52:271-293
pubmed: 30208291