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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2015

Open Access 01-12-2015 | Research

Suppression of MAPK attenuates neuronal cell death induced by activated glia-conditioned medium in alpha-synuclein overexpressing SH-SY5Y cells

Authors: Lidia M. Yshii, Alexandre Denadai-Souza, Andrea R. Vasconcelos, Maria Christina W. Avellar, Cristoforo Scavone

Published in: Journal of Neuroinflammation | Issue 1/2015

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Abstract

Background

Parkinson’s disease (PD) is a neurodegenerative disease with characteristics and symptoms that are well defined. Nevertheless, its aetiology remains unknown. PD is characterized by the presence of Lewy bodies inside neurons. α-Synuclein (α-syn) is a soluble protein present in the pre-synaptic terminal of neurons. Evidence suggests that α-syn has a fundamental role in PD pathogenesis, given that it is an important component of Lewy bodies localized in the dopaminergic neurons of PD patients.

Methods

In the present study, we investigated the influence of wild type (WT) and A30P α-syn overexpression on neuroblastoma SH-SY5Y toxicity induced by the conditioned medium (CM) from primary cultures of glia challenged with lipopolysaccharide (LPS) from Escherichia coli.

Results

We observed that SH-SY5Y cells transduced with α-syn (WT or A30P) and treated with CM from LPS-activated glia cells show evidence of cell death, which is not reverted by NF-κB inhibition by sodium salicylate or by blockage of P50 (NF-κB subunit). Furthermore, the expression of A30P α-syn in neuroblastoma SH-SY5Y decreases the cell death triggered by the CM of activated glia versus WT α-syn or control group. This effect of A30P α-syn may be due to the low MAPK42/44 phosphorylation. This finding is substantiated by MEK1 inhibition by PD98059, decreasing LDH release by CM in SH-SY5Y cells.

Conclusion

Our results suggest that SH-SY5Y cells transduced with α-syn (WT or A30P) and treated with CM from LPS-activated glia cells show cell death, which is not reverted by NF-κB blockage. Additionally, the expression of A30P α-syn on neuroblastoma SH-SY5Y leads to decreased cell death triggered by the CM of activated glia, when compared to WT α-syn or control group. The mechanism underlying this process remains to be completely elucidated, but the present data suggest that MAPK42/44 phosphorylation plays an important role in this process.

Trial Registration

PROSPERO: CRD42015020829
Literature
1.
2.
Bartus RT, Baumann TL, Siffert J, Herzog CD, Alterman R, Boulis N, et al. Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Neurology. 2013;80:1698–701.PubMedCentralCrossRefPubMed
3.
4.
Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci U S A. 1998;95:6469–73.PubMedCentralCrossRefPubMed
5.
Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.CrossRefPubMed
6.
Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH. Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci. 2004;24:6715–23.CrossRefPubMed
7.
Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, et al. Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron. 2010;65:66–79.PubMedCentralCrossRefPubMed
8.
Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet. 2004;364:1167–9.CrossRefPubMed
9.
Fuchs J, Nilsson C, Kachergus J, Munz M, Larsson EM, Schule B, et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology. 2007;68:916–22.CrossRefPubMed
10.
Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet. 1998;18:106–8.CrossRefPubMed
11.
Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–7.CrossRefPubMed
12.
Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004;55:164–73.CrossRefPubMed
13.
Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet. 2009;41:1308–12.PubMedCentralCrossRefPubMed
14.
Block ML, Hong JS. Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol. 2005;76:77–98.CrossRefPubMed
15.
McGeer PL, Itagaki S, Akiyama H, McGeer EG. Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol. 1988;24:574–6.CrossRefPubMed
16.
Kurkowska-Jastrzebska I, Wronska A, Kohutnicka M, Czlonkowski A, Czlonkowska A. The inflammatory reaction following 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine intoxication in mouse. Exp Neurol. 1999;156:50–61.CrossRefPubMed
17.
Benner EJ, Banerjee R, Reynolds AD, Sherman S, Pisarev VM, Tsiperson V, et al. Nitrated alpha-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS One. 2008;3:e1376.PubMedCentralCrossRefPubMed
18.
Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol. 2005;57:168–75.CrossRefPubMed
19.
Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 2009;8:382–97.CrossRefPubMed
20.
Hunot S, Boissiere F, Faucheux B, Brugg B, Mouatt-Prigent A, Agid Y, et al. Nitric oxide synthase and neuronal vulnerability in Parkinson’s disease. Neuroscience. 1996;72:355–63.CrossRefPubMed
21.
22.
Bonizzi G, Karin M. The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol. 2004;25:280–8.CrossRefPubMed
23.
Pasparakis M, Luedde T, Schmidt-Supprian M. Dissection of the NF-kappaB signalling cascade in transgenic and knockout mice. Cell Death Differ. 2006;13:861–72.CrossRefPubMed
24.
Ghosh A, Roy A, Liu X, Kordower JH, Mufson EJ, Hartley DM, et al. Selective inhibition of NF-kappaB activation prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease. Proc Natl Acad Sci U S A. 2007;104:18754–9.PubMedCentralCrossRefPubMed
25.
Kaltschmidt B, Uherek M, Volk B, Baeuerle PA, Kaltschmidt C. Transcription factor NF-kappaB is activated in primary neurons by amyloid beta peptides and in neurons surrounding early plaques from patients with Alzheimer disease. Proc Natl Acad Sci U S A. 1997;94:2642–7.PubMedCentralCrossRefPubMed
26.
Kawamoto EM, Lepsch LB, Boaventura MF, Munhoz CD, Lima LS, Yshii LM, et al. Amyloid beta-peptide activates nuclear factor-kappaB through an N-methyl-D-aspartate signaling pathway in cultured cerebellar cells. J Neurosci Res. 2008;86:845–60.CrossRefPubMed
27.
Camandola S, Mattson MP. NF-kappa B as a therapeutic target in neurodegenerative diseases. Expert Opin Ther Targets. 2007;11:123–32.CrossRefPubMed
28.
Tiscornia G, Singer O, Verma IM. Production and purification of lentiviral vectors. Nat Protoc. 2006;1:241–5.CrossRefPubMed
29.
Rath M, Fohr KJ, Weigt HU, Gauss A, Engele J, Georgieff M, et al. Etomidate reduces glutamate uptake in rat cultured glial cells: involvement of PKA. Br J Pharmacol. 2008;155:925–33.PubMedCentralCrossRefPubMed
30.
Larsen KE, Fon EA, Hastings TG, Edwards RH, Sulzer D. Methamphetamine-induced degeneration of dopaminergic neurons involves autophagy and upregulation of dopamine synthesis. J Neurosci. 2002;22:8951–60.PubMed
31.
Koh JY, Choi DW. Quantitative determination of glutamate mediated cortical neuronal injury in cell culture by lactate dehydrogenase efflux assay. J Neurosci Methods. 1987;20:83–90.CrossRefPubMed
32.
Lepsch LB, Munhoz CD, Kawamoto EM, Yshii LM, Lima LS, Curi-Boaventura MF, et al. Cocaine induces cell death and activates the transcription nuclear factor kappa-B in PC12 cells. Mol Brain. 2009;2:3.PubMedCentralCrossRefPubMed
33.
Kopp E, Ghosh S. Inhibition of NF-kappa B by sodium salicylate and aspirin. Science. 1994;265:956–9.CrossRefPubMed
34.
Grilli M, Pizzi M, Memo M, Spano P. Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation. Science. 1996;274:1383–5.CrossRefPubMed
35.
Cai T, Yao T, Zheng G, Chen Y, Du K, Cao Y, et al. Manganese induces the overexpression of alpha-synuclein in PC12 cells via ERK activation. Brain Res. 2010;1359:201–7.CrossRefPubMed
36.
Beraud D, Hathaway HA, Trecki J, Chasovskikh S, Johnson DA, Johnson JA, et al. Microglial activation and antioxidant responses induced by the Parkinson’s disease protein alpha-synuclein. J Neuroimmune Pharmacol. 2013;8:94–117.PubMedCentralCrossRefPubMed
37.
Banati RB, Daniel SE, Blunt SB. Glial pathology but absence of apoptotic nigral neurons in long-standing Parkinson’s disease. Mov Disord. 1998;13:221–7.CrossRefPubMed
38.
Nagatsu T, Mogi M, Ichinose H, Togari A. Changes in cytokines and neurotrophins in Parkinson’s disease. J Neural Transm Suppl. 2000;(60):277-290
39.
Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci. 2007;10:615–22.PubMedCentralCrossRefPubMed
40.
Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci. 2007;10:608–14.PubMedCentralCrossRefPubMed
41.
Gentle IE, Wong WW, Evans JM, Bankovacki A, Cook WD, Khan NR, et al. In TNF-stimulated cells, RIPK1 promotes cell survival by stabilizing TRAF2 and cIAP1, which limits induction of non-canonical NF-kappaB and activation of caspase-8. J Biol Chem. 2011;286:13282–91.PubMedCentralCrossRefPubMed
42.
Varfolomeev E, Goncharov T, Maecker H, Zobel K, Komuves LG, Deshayes K, et al. Cellular inhibitors of apoptosis are global regulators of NF-kappaB and MAPK activation by members of the TNF family of receptors. Sci Signal. 2012;5:ra22.CrossRefPubMed
43.
Lazaro DF, Rodrigues EF, Langohr R, Shahpasandzadeh H, Ribeiro T, Guerreiro P, et al. Systematic comparison of the effects of alpha-synuclein mutations on its oligomerization and aggregation. PLoS Genet. 2014;10:e1004741.PubMedCentralCrossRefPubMed
44.
Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science. 1996;274:782–4.CrossRefPubMed
45.
46.
Taha TA, Kitatani K, Bielawski J, Cho W, Hannun YA, Obeid LM. Tumor necrosis factor induces the loss of sphingosine kinase-1 by a cathepsin B-dependent mechanism. J Biol Chem. 2005;280:17196–202.CrossRefPubMed
47.
Sarnico I, Lanzillotta A, Boroni F, Benarese M, Alghisi M, Schwaninger M, et al. NF-kappaB p50/RelA and c-Rel-containing dimers: opposite regulators of neuron vulnerability to ischaemia. J Neurochem. 2009;108:475–85.CrossRefPubMed
Metadata
Title
Suppression of MAPK attenuates neuronal cell death induced by activated glia-conditioned medium in alpha-synuclein overexpressing SH-SY5Y cells
Authors
Lidia M. Yshii
Alexandre Denadai-Souza
Andrea R. Vasconcelos
Maria Christina W. Avellar
Cristoforo Scavone
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2015
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-015-0412-7

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