Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson's disease patients.
Journal
NPJ Parkinson's disease
ISSN: 2373-8057
Titre abrégé: NPJ Parkinsons Dis
Pays: United States
ID NLM: 101675390
Informations de publication
Date de publication:
10 Aug 2022
10 Aug 2022
Historique:
received:
12
05
2021
accepted:
11
07
2022
entrez:
10
8
2022
pubmed:
11
8
2022
medline:
11
8
2022
Statut:
epublish
Résumé
Several mutations that cause Parkinson's disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.
Identifiants
pubmed: 35948563
doi: 10.1038/s41531-022-00366-z
pii: 10.1038/s41531-022-00366-z
pmc: PMC9365794
doi:
Types de publication
Journal Article
Langues
eng
Pagination
103Subventions
Organisme : NCI NIH HHS
ID : P30 CA014195
Pays : United States
Organisme : Association for Academic Surgery Foundation (AASF)
ID : 0
Organisme : CSRD VA
ID : 1
Pays : United States
Informations de copyright
© 2022. The Author(s).
Références
Cell Stem Cell. 2021 Sep 2;28(9):1533-1548.e6
pubmed: 33910058
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Exp Cell Res. 2008 Jun 10;314(10):2055-65
pubmed: 18445495
Science. 1997 Jun 27;276(5321):2045-7
pubmed: 9197268
Brain Res. 1977 May 13;126(3):397-42
pubmed: 861729
Nat Neurosci. 2007 Jun;10(6):702-11
pubmed: 17515902
Biomolecules. 2015 Jul 16;5(3):1467-79
pubmed: 26193328
Cereb Cortex. 2007 Jun;17(6):1292-306
pubmed: 16835294
Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3679-E3688
pubmed: 28416701
J Vis Exp. 2017 May 7;(123):
pubmed: 28518110
Parkinsonism Relat Disord. 2009 Nov;15(9):627-32
pubmed: 19632874
J Neurosci Res. 2010 Jun;88(8):1764-76
pubmed: 20029978
Science. 2003 Oct 31;302(5646):841
pubmed: 14593171
J Biol Chem. 2004 Feb 6;279(6):4625-31
pubmed: 14627698
Science. 2012 Nov 16;338(6109):949-53
pubmed: 23161999
Nat Protoc. 2009;4(1):44-57
pubmed: 19131956
Brain. 2007 Mar;130(Pt 3):799-815
pubmed: 17303591
Cell. 2012 Jan 20;148(1-2):46-57
pubmed: 22265401
Neuron. 2018 Oct 10;100(1):75-90.e5
pubmed: 30308173
BMC Biol. 2018 Sep 10;16(1):100
pubmed: 30200940
Front Neurosci. 2018 Feb 19;12:80
pubmed: 29515354
J Neurosci. 2007 Feb 7;27(6):1405-10
pubmed: 17287515
J Neuropsychiatry Clin Neurosci. 2002 Spring;14(2):223-36; discussion 222
pubmed: 11983801
J Cell Biol. 1983 May;96(5):1374-88
pubmed: 6404912
Proc Natl Acad Sci U S A. 2015 May 19;112(20):E2725-34
pubmed: 25870293
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2693-8
pubmed: 18258746
Nat Genet. 1998 Feb;18(2):106-8
pubmed: 9462735
Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9
pubmed: 15451224
Stem Cell Reports. 2017 Jul 11;9(1):149-161
pubmed: 28579395
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19492-7
pubmed: 19033459
J Biol Chem. 2002 Jan 4;277(1):486-91
pubmed: 11679592
Hippocampus. 2012 May;22(5):954-68
pubmed: 20882551
J Neurosci. 2011 Feb 9;31(6):2225-37
pubmed: 21307259
Nat Neurosci. 2009 Jul;12(7):826-8
pubmed: 19503083
Parkinsonism Relat Disord. 2016 Jan;22 Suppl 1:S1-6
pubmed: 26350119
J Neurosci. 2009 Jul 22;29(29):9210-8
pubmed: 19625511
Front Mol Neurosci. 2014 May 27;7:49
pubmed: 24904275
Channels (Austin). 2009 Jul-Aug;3(4):233-8
pubmed: 19690465
Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
pubmed: 12498954
J Vis Exp. 2014 Sep 15;(91):51737
pubmed: 25285746
Clin Neuropharmacol. 1999 Jul-Aug;22(4):213-5
pubmed: 10442250
Neurology. 2009 Jul 28;73(4):279-86
pubmed: 19636047
Clin Genet. 2007 May;71(5):471-3
pubmed: 17489854
Handb Clin Neurol. 2018;147:211-227
pubmed: 29325612
Mol Neurodegener. 2014 Nov 12;9:47
pubmed: 25391693
Nat Neurosci. 2019 Feb;22(2):243-255
pubmed: 30617258
Neurochem Res. 2014;39(3):576-92
pubmed: 23729298
Trends Genet. 2018 Jan;34(1):65-78
pubmed: 29102406
Ann Neurol. 2010 Apr;67(4):550
pubmed: 20437592
Hum Mol Genet. 2009 Nov 15;18(22):4390-404
pubmed: 19692353
EMBO J. 2004 Nov 10;23(22):4506-16
pubmed: 15510220
Acta Neuropathol Commun. 2017 Feb 1;5(1):11
pubmed: 28143577
Adv Exp Med Biol. 2012;970:553-72
pubmed: 22351072
Brain Res Dev Brain Res. 1997 Mar 17;99(1):87-94
pubmed: 9088569
Eur Neurol. 1988;28 Suppl 1:15-23
pubmed: 3288478
Ann Neurol. 2004 Feb;55(2):164-73
pubmed: 14755719
Science. 1980 Aug 15;209(4458):809-10
pubmed: 7403847
N Engl J Med. 2000 May 25;342(21):1560-7
pubmed: 10824074
Neuron. 2010 Jan 14;65(1):66-79
pubmed: 20152114
Nature. 2011 Nov 06;480(7378):547-51
pubmed: 22056989
J Neurosci. 2002 Apr 1;22(7):2780-91
pubmed: 11923443
Biol Psychiatry. 2020 Jul 15;88(2):150-158
pubmed: 32278494
J Neurosci. 2019 Sep 11;39(37):7438-7449
pubmed: 31350261
Mol Psychiatry. 2016 Nov;21(11):1573-1588
pubmed: 27698428
Hum Mol Genet. 2017 Aug 1;26(15):2933-2948
pubmed: 28482024
Cell Stem Cell. 2015 Dec 3;17(6):705-718
pubmed: 26456686
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Biochem Soc Trans. 2010 Apr;38(2):493-7
pubmed: 20298209
J Neurosci. 2000 May 1;20(9):3214-20
pubmed: 10777786
Hum Mutat. 2010 Jul;31(7):763-80
pubmed: 20506312
Sci Rep. 2016 Jul 27;6:30509
pubmed: 27461410
J Neurochem. 2001 Jul;78(1):42-54
pubmed: 11432972
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Ann Neurol. 1990 Mar;27(3):276-82
pubmed: 2158268
Genome Biol. 2002;3(1):REVIEWS3002
pubmed: 11806835
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14622-7
pubmed: 19667187
Mol Cell. 2010 May 28;38(4):576-89
pubmed: 20513432
Eur Neuropsychopharmacol. 2005 Aug;15(4):473-90
pubmed: 15963700
Mol Cell. 2009 Dec 25;36(6):1034-47
pubmed: 20064468
Brain. 2017 Sep 1;140(9):2265-2272
pubmed: 28335015
J Neurosci. 2004 Dec 8;24(49):11165-70
pubmed: 15590933
Nature. 2001 Feb 15;409(6822):860-921
pubmed: 11237011
Parkinsonism Relat Disord. 2011 Aug;17(7):501-8
pubmed: 21641266
PLoS One. 2011;6(11):e26159
pubmed: 22110584
PLoS One. 2013 Aug 01;8(8):e70274
pubmed: 23936403
EMBO J. 2018 Sep 14;37(18):
pubmed: 30065071
Transl Neurodegener. 2015 Nov 03;4:21
pubmed: 26535116
J Neural Transm (Vienna). 2017 Aug;124(8):901-905
pubmed: 28150045
Hum Genet. 2009 Jan;124(6):593-605
pubmed: 18985386
Nature. 2011 May 12;473(7346):221-5
pubmed: 21490598
J Neurosci. 2014 Feb 5;34(6):2037-50
pubmed: 24501346
Ann Neurol. 2010 Jun;67(6):715-25
pubmed: 20517933
Neurology. 1998 Aug;51(2 Suppl 2):S2-9
pubmed: 9711973
Ann Neurol. 2008 Nov;64(5):485-91
pubmed: 19067353
Elife. 2016 Aug 15;5:
pubmed: 27525480
J Parkinsons Dis. 2015;5(4):699-713
pubmed: 26407041
NPJ Parkinsons Dis. 2020 Apr 24;6:8
pubmed: 32352027
Hum Mol Genet. 2002 Oct 1;11(20):2395-407
pubmed: 12351575
Neurology. 2007 Mar 20;68(12):916-22
pubmed: 17251522
Cold Spring Harb Perspect Med. 2012 Feb;2(2):a009399
pubmed: 22355802
Mov Disord. 2012 Jun;27(7):831-42
pubmed: 22451330
Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3213-9
pubmed: 22315428
J Neurosci. 2012 Jul 25;32(30):10129-35
pubmed: 22836248
Exp Neurol. 2013 Aug;246:72-83
pubmed: 22285449
Neuron. 2018 Oct 24;100(2):276-293
pubmed: 30359597