Alpha-synuclein activates the classical complement pathway and mediates complement-dependent cell toxicity.
Complement system
Cp20
MSA
Neurodegeneration
RaCI
SH-SY5Y
α-Synuclein
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
16 Aug 2021
16 Aug 2021
Historique:
received:
12
01
2021
accepted:
21
07
2021
entrez:
17
8
2021
pubmed:
18
8
2021
medline:
14
1
2022
Statut:
epublish
Résumé
Synucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer's disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology. To investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients. We demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls. α-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.
Sections du résumé
BACKGROUND
BACKGROUND
Synucleinopathies are characterized by neurodegeneration and deposition of the presynaptic protein α-synuclein in pathological protein inclusions. Growing evidence suggests the complement system not only has physiological functions in the central nervous system, but also is involved in mediating the pathological loss of synapses in Alzheimer's disease. However, it is not established whether the complement system has a similar role in the diseases Parkinson's disease, Dementia with Lewy bodies, and multiple system atrophy (MSA) that are associated with α-synuclein aggregate pathology.
METHODS
METHODS
To investigate if the complement system has a pathological role in synucleinopathies, we assessed the effect of the complement system on the viability of an α-synuclein expressing cell model and examined direct activation of the complement system by α-synuclein in a plate-based activation assay. Finally, we investigated the levels of the initiator of the classical pathway, C1q, in postmortem brain samples from MSA patients.
RESULTS
RESULTS
We demonstrate that α-synuclein activates the classical complement pathway and mediates complement-dependent toxicity in α-synuclein expressing SH-SY5Y cells. The α-synuclein-dependent cellular toxicity was rescued by the complement inhibitors RaCI (inhibiting C5) and Cp20 (inhibiting C3). Furthermore, we observed a trend for higher levels of C1q in the putamen of MSA subjects than that of controls.
CONCLUSION
CONCLUSIONS
α-Synuclein can activate the classical complement pathway, and the complement system is involved in α-synuclein-dependent cellular cytotoxicity suggesting the system could play a prodegenerative role in synucleinopathies.
Identifiants
pubmed: 34399786
doi: 10.1186/s12974-021-02225-9
pii: 10.1186/s12974-021-02225-9
pmc: PMC8369722
doi:
Substances chimiques
alpha-Synuclein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
177Subventions
Organisme : Lundbeckfonden
ID : R223-2015-4222
Organisme : Lundbeckfonden
ID : R248-2016-2518
Organisme : National Health and Medical Research Council
ID : 1176607
Organisme : Novo Nordisk Fonden
ID : Distinguished Innovator 1-2020 grant
Organisme : EU Multinational research projects on Personalised Medicine for Neurodegenerative Diseases
ID : JPND2019
Informations de copyright
© 2021. The Author(s).
Références
Mol Neurodegener. 2012 Aug 24;7:42
pubmed: 22920859
Mov Disord. 2008 Dec 15;23(16):2303-6
pubmed: 19006193
Science. 2016 Sep 30;353(6307):
pubmed: 27708076
Mov Disord. 2004 Dec;19(12):1391-402
pubmed: 15452868
Acta Neuropathol Commun. 2014 Oct 29;2:150
pubmed: 25358962
J Clin Invest. 2009 Jan;119(1):182-92
pubmed: 19104149
J Leukoc Biol. 2020 Jul;108(1):339-351
pubmed: 32182389
J Immunol. 1981 Aug;127(2):648-53
pubmed: 7252154
J Immunol Methods. 1993 Jul 6;163(1):67-76
pubmed: 7687639
EMBO J. 2015 Nov 12;34(22):2735-57
pubmed: 26489954
Cold Spring Harb Perspect Med. 2012 Feb;2(2):a009399
pubmed: 22355802
J Proteome Res. 2021 Jul 2;20(7):3428-3443
pubmed: 34061533
Nat Commun. 2013;4:1562
pubmed: 23463005
J Biol Chem. 2005 Feb 18;280(7):5703-15
pubmed: 15590652
PLoS One. 2015 Feb 06;10(2):e0116473
pubmed: 25659148
Eur J Clin Invest. 2015 Apr;45(4):423-40
pubmed: 25678219
Ann Neurol. 2005 Dec;58(6):963-7
pubmed: 16240369
Mol Psychiatry. 1998 Nov;3(6):462-5
pubmed: 9857966
Biochem Biophys Res Commun. 2007 Jun 15;357(4):1096-9
pubmed: 17459337
Am J Pathol. 2011 Apr;178(4):1509-16
pubmed: 21435440
J Biol Chem. 1990 Aug 25;265(24):14469-75
pubmed: 2387866
Front Immunol. 2018 Nov 20;9:2664
pubmed: 30515158
Annu Rev Neurosci. 2012;35:369-89
pubmed: 22715882
Science. 2016 May 6;352(6286):712-716
pubmed: 27033548
Nat Neurosci. 2017 May;20(5):681-689
pubmed: 28288128
Dis Markers. 2005;21(2):93-101
pubmed: 15920296
J Neurosci Res. 1995 Mar 1;40(4):478-93
pubmed: 7616608
Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
pubmed: 12498954
J Biol Chem. 1999 Sep 3;274(36):25481-9
pubmed: 10464279
Am J Pathol. 2011 Aug;179(2):954-63
pubmed: 21801874
J Neurosci. 2002 Oct 15;22(20):8797-807
pubmed: 12388586
Nat Neurosci. 2017 Nov;20(11):1569-1579
pubmed: 28945221
Nat Med. 2008 May;14(5):501-3
pubmed: 18391963
Neurology. 2010 Mar 23;74(12):995-1002
pubmed: 20308684
Nat Struct Mol Biol. 2016 May;23(5):378-86
pubmed: 27018802
Cell. 2007 Dec 14;131(6):1164-78
pubmed: 18083105
Glia. 2003 Jun;42(4):417-23
pubmed: 12730962
Neurology. 1988 Aug;38(8):1285-91
pubmed: 3399080
Nat Rev Drug Discov. 2019 Sep;18(9):707-729
pubmed: 31324874
J Immunol Methods. 1983 Apr 29;59(2):229-35
pubmed: 6841978
Acta Neuropathol. 1992;84(1):100-4
pubmed: 1502878
EMBO Rep. 2018 May;19(5):
pubmed: 29599149
Parkinsonism Relat Disord. 1999 Dec;5(4):157-62
pubmed: 18591134
Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10427-32
pubmed: 16020533
J Neuroinflammation. 2006 Oct 19;3:29
pubmed: 17052351
Redox Biol. 2018 Apr;14:600-608
pubmed: 29154191
Mol Med. 2011 Mar-Apr;17(3-4):317-29
pubmed: 21046060
Nat Rev Neurosci. 2019 Dec;20(12):728-745
pubmed: 31712781
J Neurochem. 2009 Jun;109(5):1348-62
pubmed: 19476547
Brain Res. 1997 Sep 26;769(2):391-5
pubmed: 9374212
Molecules. 2019 Jan 15;24(2):
pubmed: 30650656
Neuron. 2012 May 24;74(4):691-705
pubmed: 22632727