Alpha-synuclein proteins promote pro-inflammatory cascades in microglia: Stronger effects of the a53t mutant

PLoS ONE

Volumn 11, Issue 9, 2016, Pages

  Hoenen, Claire ^a   Gustin, Audrey ^a   Birck, Cindy ^a   Kirchmeyer, Mélanie ^a   Beaume, Nicolas ^a   Felten, Paul ^a   Grandbarbe, Luc ^a   Heuschling, Paul ^a   Heurtaux, Tony ^a  

^a UNIVERSITY OF LUXEMBOURG   (Luxembourg)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE; ALPHA SYNUCLEIN; GLUTAMIC ACID; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; LYSINE; MITOGEN ACTIVATED PROTEIN KINASE; MUTANT PROTEIN; PEPTIDE; PROLINE; THREONINE; TRANSCRIPTION FACTOR NRF2; AUTACOID; REACTIVE OXYGEN METABOLITE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CONTROLLED STUDY; ENZYME ACTIVITY; MICROGLIA; MOUSE; NERVE CELL STIMULATION; NERVOUS SYSTEM INFLAMMATION; NEWBORN; NONHUMAN; PARKINSON DISEASE; PATHOGENESIS; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; TRANSCRIPTION INITIATION; AMINO ACID SUBSTITUTION; ANIMAL; CELL CULTURE; GENE EXPRESSION; GENETICS; HUMAN; INFLAMMATION; METABOLISM; PATHOLOGY; POINT MUTATION; SIGNAL TRANSDUCTION;

ALPHA-SYNUCLEIN; AMINO ACID SUBSTITUTION; ANIMALS; CELLS, CULTURED; GENE EXPRESSION; HUMANS; INFLAMMATION; INFLAMMATION MEDIATORS; MICE; MICROGLIA; MUTANT PROTEINS; PARKINSON DISEASE; POINT MUTATION; REACTIVE OXYGEN SPECIES; SIGNAL TRANSDUCTION;

EID: 84990888249     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0162717     Document Type: Article

References (85)

1. Pfeiffer RF. Non-motor symptoms in Parkinson's disease. Park Relat Disord. Elsevier Ltd; 2016; 22: S119-S122. doi: 10.1016/j.parkreldis.2015.09.004
2. Korlipara L, Schapira A. Parkinson's Disease. Int Rev Neurobiol. 2002; 53: 283-314. PMID: 12512344
3. Lundblad M, Decressac M, Mattsson B, Björklund A. Impaired neurotransmission caused by overexpression of α -synuclein in nigral dopamine neurons. Proc Natl Acad Sci U S A. 2012; 109: 3213-3219. doi: 10.1073/pnas.1200575109 PMID: 22315428
4. Lashuel HA, Overk CR, Oueslati A ME. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2013; 14: 38-48. doi: 10.1038/nrn3406 PMID: 23254192
5. Totterdell S, Hanger D, Meredith GE. The ultrastructural distribution of alpha-synuclein-like protein in normal mouse brain. Brain Res. 2004; 1004: 61-72. doi: 10.1016/j.brainres.2003.10.072 PMID: 15033420
6. Totterdell S, Meredith GE. Localization of alpha-synuclein to identified fibers and synapses in the normal mouse brain. Neuroscience. 2005; 135: 907-913. doi: 10.1016/j.neuroscience.2005.06.047 PMID: 16112475
7. Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primaryhippocampal neurons. J Neurosci. 2000; 20: 3214-3220. PMID: 10777786
8. Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci. 2001; 2: 492-501. doi: 10.1038/35081564 PMID: 11433374
9. Martin FL, Williamson SJ, Paleologou KE, Allsop D E-AO. Alpha-synuclein and the pathogenesis of Parkinson's disease. Protein Pept Lett. 2004; 11: 229-37. PMID: 15182224
10. Caughey B, Lansbury PT. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci. 2003; 26: 267-298. doi: 10. 1146/annurev.neuro.26.010302.081142 PMID: 12704221
11. Danzer KM, Haasen D, Karow AR, Moussaud S, Habeck M, Giese A, et al. Different species of alphasynuclein oligomers induce calcium influx and seeding. J Neurosci. 2007; 27: 9220-9232. doi: 10. 1523/JNEUROSCI.2617-07.2007 PMID: 17715357
12. Winner B, Jappelli R, Maji SK, Desplats PA, Boyer L, Aigner S. In vivo demonstration that α-synuclein oligomers are toxic. PNAS. 2011; 108: 4194-4199. doi: 10.1073/pnas.1100976108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1100976108 PMID: 21325059
13. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J. 2005; 19: 533-42. doi: 10.1096/fj.04-2751com PMID: 15791003
14. 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 (80-). 1997; 276: 2045-2047. doi: 10.1126/science.276.5321.2045 PMID: 9197268
15. Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet. 1998; 18: 106-108. doi: 10.1038/ ng0298-106 PMID: 9462735
16. Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, et al. The New Mutation, E46K, of α-Synuclein Causes Parkinson and Lewy Body Dementia. Ann Neurol. 2004; 55: 164-173. doi: 10.1002/ana.10795 PMID: 14755719
17. Fredenburg R a., Rospigliosi C, Meray RK, Kessler JC, Lashuel H a., Eliezer D, et al. The impact of the E46K mutation on the propertiesof α-synuclein in its monomeric and oligomeric states. Biochemistry. 2007; 46: 7107-7118. doi: 10.1021/bi7000246 PMID: 17530780
18. Ghosh D, Sahay S, Ranjan P, Salot S, Mohite GM, Singh PK, et al. The Newly Discovered Parkinson's Disease Associated Finnish Mutation (A53E) Attenuates α Synuclein Aggregation and Membrane Binding. Biochemistry. 2014; 53: 6419-6421. doi: 10.1021/bi5010365 PMID: 25268550
19. Khalaf O, Fauvet B, Oueslati A, Dikiy I, Mahul-Mellier AL, Ruggeri FS, et al. The H50Q mutation enhances αα-synuclein aggregation, secretion, and toxicity. J Biol Chem. 2014; 289: 21856-21876. doi: 10.1074/jbc.M114.553297 PMID: 24936070
20. Kiely AP, Asi YT, Kara E, Limousin P, Ling H, Lewis P, et al. A-synucleinopathy associated with G51D SNCA mutation: A link between Parkinson's disease and multiple system atrophy? Acta Neuropathol. 2013; 125: 753-769. doi: 10.1007/s00401-013-1096-7 PMID: 23404372
21. Marques O, Outeiro TF. Alpha-synuclein: from secretion to dysfunction and death. Cell Death Dis. Nature Publishing Group; 2012; 3: e350. doi: 10.1038/cddis.2012.94 PMID: 22825468
22. El-Agnaf OM, Salem S, Paleologou KE, Cooper LJ, Fullwood NJ, Gibson MJ, et al. Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J. 2003; 17: 1945-1947. doi: 10.1096/fj.03-0098fje PMID: 14519670
23. Borghi R, Marchese R, Negro A, Marinelli L, Forloni G, Zaccheo D, et al. Full length alpha-synuclein is present in cerebrospinal fluid from Parkinson's disease and normal subjects. Neurosci Lett. 2000; 287: 65-67. doi: 10.1016/S0304-3940(00)01153-8 PMID: 10841992
24. Lee HJ, Suk JE, Bae EJ, Lee SJ. Clearance and deposition of extracellular α-synuclein aggregates in microglia. Biochem Biophys Res Commun. 2008; 372: 423-428. doi: 10.1016/j.bbrc.2008.05.045 PMID: 18492487
25. Béraud 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 α-Synuclein. J Neuroimmune Pharmacol. 2013; 8: 94-117. doi: 10.1007/s11481-012-9401-0 PMID: 23054368
26. Wilkaniec A, Strosznajder JB, Adamczyk A. Toxicity of extracellular secreted alpha-synuclein: Its role in nitrosative stress and neurodegeneration. Neurochem Int. Elsevier Ltd; 2013; 62: 776-783. doi: 10. 1016/j.neuint.2013.02.004 PMID: 23416621
27. Tang Y, Le W. Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases. Mol Neurobiol. 2015; doi: 10.1007/s12035-014-9070-5
28. Michelucci A, Heurtaux T, Grandbarbe L, Morga E, Heuschling P. Characterization of the microglial phenotype under specific pro-inflammatory and anti-inflammatory conditions: Effects of oligomeric and fibrillar amyloid-beta. J Neuroimmunol. 2009; 210: 3-12. doi: 10.1016/j.jneuroim.2009.02.003 PMID: 19269040
29. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996; 19: 312-318. PMID: 8843599
30. Tansey MG, McCoy MK, and Frank-Cannon TC. Neuroinflammatory mechanisms in Parkinson's disease: Potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol. 2007; 208: 1-25. doi: 10.1016/j.expneurol.2007.07.004 PMID: 17720159
31. Galimberti D, Schoonenboom N, Scheltens P, Fenoglio C, Bouwman F, Venturelli E, et al. Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. ArchNeurol. 2006; 63: 538-543.
32. Franco R, Fernandez-Suarez D. Alternatively activated microglia and macrophages in the central nervous system. Prog Neurobiol. 2015; 131: 65-86. doi: 10.1016/j.pneurobio.2015.05.003 PMID: 26067058
33. Frank-Cannon TC, Alto LT, McAlpine FE, Tansey MG. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol Neurodegener. 2009; 4: 47. doi: 10.1186/1750-1326-4-47 PMID: 19917131
34. Losciuto S, Dorban G, Gabel S, Gustin A, Hoenen C, Grandbarbe L, et al. An efficient method to limit microglia-dependent effects in astroglial cultures. J Neurosci Methods. 2012; 207: 59-71. doi: 10.1016/ j.jneumeth.2012.03.010 PMID: 22483759
35. Perry VH. Innate Inflammation in Parkinson's Disease. Cold Spring Harb Perspect Med. 2012; 2: a009373. doi: 10.1101/cshperspect.a009373 PMID: 22951445
36. McGeer P, Yasojima K, McGeer E. Inflammation in Parkinson's disease. Adv Neurol. 2001; 86: 83-89. PMID: 11554012
37. Vivekanantham S, Shah S, Dewji R, Dewji A, Khatri C, Ologunde R. Neuroinflammation in Parkinson's disease: role in neurodegeneration and tissue repair. Int J Neurosci. 2015; 125: 717-725. doi: 10.3109/ 00207454.2014.982795 PMID: 25364880
38. Lee JK, Tran T, Tansey MG. Neuroinflammation in Parkinson's disease. J Neuroimmune Pharmacol. 2009; 4: 419-429. doi: 10.1007/s11481-009-9176-0 PMID: 19821032
39. Sanchez-Guajardo V, Barnum CJ, Tansey MG, Romero-Ramos M. Neuroimmunological processes in Parkinson's disease and their relation to α-synuclein: microglia as the referee between neuronal processes and peripheral immunity. ASN Neuro. 2013; 5: 113-39. doi: 10.1042/AN20120066 PMID: 23506036
40. Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson's disease and its potential as therapeutic target. Transl Neurodegener. Translational Neurodegeneration; 2015; 4: 19. doi: 10.1186/s40035-015-0042-0 PMID: 26464797
41. Stefanis L. α-Synuclein in Parkinson's Disease. Cold Spring Harb Perspect Med. 2012; 4: a009399. doi: 10.1101/cshperspect.a009399
42. Barrett PJ, Timothy Greenamyre J. Post-translational modification of alpha-synuclein in Parkinson's disease. Brain Res. Elsevier; 2015; 1628: 247-253. doi: 10.1016/j.brainres.2015.06.002 PMID: 26080075
43. Roodveldt C, Labrador-Garrido A, Gonzalez-Rey E, Fernandez-Montesinos R, Caro M, Lachaud CC, et al. Glial Innate Immunity Generated by Non-Aggregated Alpha-Synuclein in Mouse: Differences between Wild-type and Parkinson's Disease-Linked Mutants. PLoS One. 2010; 5: e13481. doi: 10. 1371/journal.pone.0013481 PMID: 21048992
44. Alvarez-Erviti L, Couch Y, Richardson J, Cooper JM, Wood MJ. Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. Neurosci Res. Elsevier Ireland Ltd and Japan Neuroscience Society; 2011; 69: 337-42. doi: 10.1016/j.neures.2010.12.020 PMID: 21255620
45. Klegeris A, Pelech S, Giasson BI, Maguire J, Zhang H, McGeer EG, et al. Alpha-synuclein activates stress signaling protein kinases in THP-1 cells and microglia. Neurobiol Aging. 2008; 29: 739-52. doi: 10.1016/j.neurobiolaging.2006.11.013 PMID: 17166628
46. Rojanathammanee L, Murphy EJ, Combs CK. Expression of mutant alpha-synuclein modulates microglial phenotype in vitro. J Neuroinflammation. BioMed Central Ltd; 2011; 8: 44. doi: 10.1186/1742-2094-8-44 PMID: 21554732
47. Heurtaux T, Michelucci A, Losciuto S, Gallotti C, Felten P, Dorban G, et al. Microglial activation depends on beta-amyloid conformation: Role of the formylpeptide receptor 2. J Neurochem. 2010; 114: 576-586. doi: 10.1111/j.1471-4159.2010.06783.x PMID: 20456016
48. Stöckl MT, Zijlstra N, Subramaniam V. α-Synuclein Oligomers: an Amyloid Pore?-Insights into Mechanisms of α-Synuclein Oligomer-Lipid Interactions. Mol Neurobiol. 2013; 47: 613-621. doi: 10.1007/ s12035-012-8331-4 PMID: 22956232
49. Karpinar DP, Balija MBG, Kügler S, Opazo F, Rezaei-Ghaleh N, Wender N, et al. Pre-fibrillar alphasynuclein variants with impaired beta-structureincrease neurotoxicity in Parkinson's disease models. EMBO J. 2009; 28: 3256-3268. doi: 10.1038/emboj.2009.257 PMID: 19745811
50. Mahul-Mellier A-L, Vercruysse F, Maco B, Ait-Bouziad N, De Roo M, Muller D, et al. Fibril growth and seeding capacity play key roles in α-synuclein-mediated apoptotic cell death. Cell Death Differ. Nature Publishing Group; 2015; 1-16. doi: 10.1038/cdd.2015.79
51. Pieri L, Madiona K, Bousset L, Melki R. Fibrillar alpha-synuclein and huntingtin exon 1 assemblies are toxic to the cells. Biophys J. Biophysical Society; 2012; 102: 2894-2905. doi: 10.1016/j.bpj.2012.04. 050 PMID: 22735540
52. Ozansoy M, Başak AN. The Central Theme of Parkinson's Disease: α-Synuclein. Mol Neurobiol. 2013; 47: 460-465. doi: 10.1007/s12035-012-8369-3 PMID: 23180276
53. Hatano T, Kubo SI, Sato S, Hattori N. Pathogenesis of familial Parkinson's disease: New insights based on monogenic forms of Parkinson's disease. J Neurochem. 2009; 111: 1075-1093. doi: 10. 1111/j.1471-4159.2009.06403.x PMID: 19780902
54. Li J, Uversky VN, Fink AL. Effect of familial Parkinson's disease point mutations A30P and A53T on the structural properties, aggregation, and fibrillation of human alpha-synuclein. Biochemistry. 2001; 40: 11604-11613. doi: 10.1021/bi010616g PMID: 11560511
55. Sahay S, Ghosh D, Dwivedi S, Anoop A, Mohite GM, Kombrabail M, et al. Familial Parkinson Diseaseassociated Mutations Alter the Site-specific Microenvironment and Dynamics of α-Synuclein. J Biol Chem. 2015; 290: 7804-7822. doi: 10.1074/jbc.M114.598607 PMID: 25635052
56. Snead D, Eliezer D. Alpha-synuclein function and dysfunction on cellular membranes. Exp Neurobiol. 2014; 23: 292-313. doi: 10.5607/en.2014.23.4.292 PMID: 25548530
57. Reish Heather E. Allen, Standaert David G. Role of a-synuclein in inducing innate and adaptive immunity in Parkinson disease. J Park Dis. 2015; 5: 1-19.
58. Lee S, Park SM, Ahn KJ, Chung KC, Paik SR, Kim J. Identification of the amino acid sequence motif of alpha-synuclein responsible for macrophage activation. Biochem Biophys Res Commun. Elsevier Inc.; 2009; 381: 39-43. doi: 10.1016/j.bbrc.2009.02.002 PMID: 19351591
59. Harry G. Microglia During Deveopment and Aging. Pharmacol Ther. 2013 139: 313-326. doi: 10.1016/ j.pharmthera.2013.04.013 PMID: 23644076
60. Wilkinson K, El Khoury J. Microglial scavenger receptors and their roles in the pathogenesis of Alzheimer's disease. Int J Alzheimers Dis. 2012; 2012. doi: 10.1155/2012/489456
61. Hanisch U-K, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007; 10: 1387-1394. doi: 10.1038/nn1997 PMID: 17965659
62. Tóbon-Vel asco JC, Cuevas E T-RM. Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS Neurol Disord Drug Targets. 2014; 13: 1615-1626. PMID: 25106630
63. Medeiros MC De, Frasnelli SCT, Bastos ADS, Orrico SRP, Rossa C. Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: role of p38 MAPK and NF-KB. J Appl Oral Sci. 2014; 22: 185-93. doi: 10.1590/1678-775720130593 PMID: 25025559
64. Ahmad R, Shihab PK, Jasem S, Behbehani K. FSL-1 Induces MMP-9 Production through TLR-2 and NF-κB /AP-1 Signaling Pathways in Monocytic THP-1 Cells. Cell Physiol Biochem. 2014; 34: 929-942. doi: 10.1159/000366310 PMID: 25200491
65. Abdelsalam RM, Safar MM. Neuroprotective effects of vildagliptin in rat rotenone Parkinson's disease model: role of RAGE-NFκB and Nrf2-antioxidant signaling pathways. J Neurochem. 2015; 133: 700-707. doi: 10.1111/jnc.13087 PMID: 25752913
66. Aravalli RN, Hu S, Lokensgard JR. Inhibition of Toll-like receptor signaling in primarymurine microglia. J Neuroimmune Pharmacol. 2008; 3: 5-11. doi: 10.1007/s11481-007-9097-8 PMID: 18066668
67. Kim EK, Choi E-J. Compromised MAPK signaling in human diseases: an update. Arch Toxicol. Springer Berlin Heidelberg; 2015; 89: 867-882. doi: 10.1007/s00204-015-1472-2 PMID: 25690731
68. Tichauer J, Saud K, von Bernhardi R. Modulation by astrocytes of microglial cell-mediated neuroinflammation: effect on the activation of microglial signaling pathways. Neuroimmunomodulation. 2007; 14: 168-174. PMID: 18073510
69. Kim M-O, Si Q, Zhou JN, Pestell RG, Brosnan CF, Locker J, et al. Interferon-beta activates multiple signaling cascades in primaryhuman microglia. J Neurochem. 2002; 81: 1361-71. Available: http://www. ncbi.nlm.nih.gov/pubmed/12068083 PMID: 12068083
70. Couch Y, Alvarez-Erviti L, Sibson NR, Wood MJA, Anthony DC. The acute inflammatory response to intranigral α-synuclein differs significantly from intranigral lipopolysaccharide and is exacerbated by peripheral inflammation. J Neuroinflammation. 2011; 8: 166. doi: 10.1186/1742-2094-8-166 PMID: 22122884
71. Reynolds AD, Glanzer JG, Kadiu I, Ricardo-Dukelow M, Chaudhuri A, Ciborowski P, et al. Nitrated alpha-synuclein-activated microglial profiling for Parkinson's disease. J Neurochem. 2008; 104: 1504-1525. doi: 10.1111/j.1471-4159.2007.05087.x PMID: 18036154
72. Lee E-J, Woo M-S, Moon P-G, Baek M-C, Choi I-Y, Kim W-K, et al. Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of proteaseactivated receptor-1. J Immunol. 2010; 185: 615-23. doi: 10.4049/jimmunol.0903480 PMID: 20511551
73. Jeon S-B, Yoon HJ, Park S-H, Kim I-H, Park EJ. Sulfatide, a major lipid component of myelin sheath, activates inflammatory responses as an endogenous stimulator in brain-resident immune cells. J Immunol. 2008; 181: 8077-8087. doi:181/11/8077 PMID: 19018000
74. Campa VM, Iglesias JM, Carcedo MT, Rodríguez R, Riera J, Ramos S, et al. Polyinosinic acid induces TNF and NO production as well as NF-κB and AP-1 transcriptional activation in the monocyte-macrophage cell line RAW 264.7. Inflamm Res. 2005; 54: 328-337. doi: 10.1007/s00011-005-1359-4 PMID: 16158333
75. DebRoy A, Vogel SM, Soni D, Sundivakkam PC, Malik AB, Tiruppathi C. Cooperative Signaling via Transcription Factors NF- B and AP1/c-Fos Mediates Endothelial Cell STIM1 Expression and Hyperpermeability in Response to Endotoxin. J Biol Chem. 2014; 289: 24188-24201. doi: 10.1074/jbc.M114. 570051 PMID: 25016017
76. Arthur J. MSK activation and physiological roles. Front Biosci. 2008; 13: 5866-5879. PMID: 18508628
77. Delgado M, Varela N, Gonzalez-Rey E. Vasoactive intestinal peptide protects against beta-amyloidinduced neurodegeneration by inhibiting microglia activation at multiple levels. Glia. 2008; 56: 1091-1103. doi: 10.1002/glia.20681 PMID: 18442091
78. Karin M. The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem. 1995; 270: 16483-16486. PMID: 7622446
79. Johnson JA, Johnson DA, Kraft AD, Calkins MJ. The Nrf2-ARE Pathway: An Indicator and Modulator of Oxidative Stress in Neurodegeneration. Ann N Y Acad Sci. 2008; 1147: 61-69. doi: 10.1196/annals. 1427.036 PMID: 19076431
80. Lastres-Becker I, Ulusoy A, Innamorato NG, Sahin G, Rábano A, Kirik D, et al. α-Synuclein expression and Nrf2-deficiency cooperate to aggravate protein aggregation, neuronal death and inflammation in early-stage Parkinson's disease. Hum Mol Genet. 2012; 1-20. doi: 10.1093/hmg/dds143
81. Johnson DA, Johnson JA. Nrf2-a therapeutic target for the treatment of neurodegenerative diseases. Free Radic Biol Med. Elsevier; 2015; 88: 253-267. doi: 10.1016/j.freeradbiomed.2015.07.147 PMID: 26281945
82. Kim J, Cha YN, Surh YJ. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res-Fundam Mol Mech Mutagen. Elsevier B.V.; 2010; 690: 12-23. doi: 10. 1016/j.mrfmmm.2009.09.007
83. Pradhan S, Andreasson K. Commentary: Progressive inflammation as a contributing factor to early development of Parkinson's disease. Exp Neurol. Elsevier Inc.; 2013; 241: 148-155. doi: 10.1016/j. expneurol.2012.12.008 PMID: 23261765
84. Durrenberger PF, Grünblatt E, Fernando FS, Monoranu CM, Evans J, Riederer P, et al. Inflammatory Pathways in Parkinson's Disease; A BNE Microarray Study. Parkinsons Dis. 2012; 2012: 214714. doi: 10.1155/2012/214714 PMID: 22548201
85. Bliederhaeuser C, Grozdanov V, Speidel A, Zondler L, Ruf WP, Bayer H, et al. Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. Acta Neuropathol. Springer Berlin Heidelberg; 2015; 131: 1-13. doi: 10.1007/s00401-015-1504-2