Neurobiology of Aging
Volume 29, Issue 5 , Pages 739-752 , May 2008

α-Synuclein activates stress signaling protein kinases in THP-1 cells and microglia

  • Andis Klegeris

      Affiliations

    • Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
  • ,
  • Steven Pelech

      Affiliations

    • Department of Medicine, University of British Columbia, Vancouver, BC, Canada
    • Kinexus Bioinformatics Corporation, Suite 402, 6190 Agronomy Road, Vancouver, BC V6T 1Z3, Canada
  • ,
  • Benoit I. Giasson

      Affiliations

    • Department of Pharmacology, University of Pennsylvania, Philadelphia, PA, USA
  • ,
  • John Maguire

      Affiliations

    • Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
  • ,
  • Hong Zhang

      Affiliations

    • Kinexus Bioinformatics Corporation, Suite 402, 6190 Agronomy Road, Vancouver, BC V6T 1Z3, Canada
  • ,
  • Edith G. McGeer

      Affiliations

    • Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
  • ,
  • Patrick L. McGeer

      Affiliations

    • Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada
    • Corresponding Author InformationCorresponding author. Tel.: +1 604 822 7377; fax: +1 604 822 7086.

Received 30 June 2006 ,Revised 17 November 2006 ,Accepted 19 November 2006.

References 

  1. Bagrodia S, Derijard B, Davis RJ, Cerione RA. Cdc42 and PAK-mediated signaling leads to Jun kinase and p38 mitogen-activated protein kinase activation. J. Biol. Chem. 1995;270:27995–27998
  2. 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
  3. Cantrell D. Protein kinase B (Akt) regulation and function in T lymphocytes. Semin. Immunol. 2002;14:19–26
  4. Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC. Alpha-synuclein cooperates with CSPα in preventing neurodegeneration. Cell. 2005;123:383–396
  5. Charest DL, Mordret G, HK W, Jirik F, Pelech SL. Molecular cloning, expression, and characterization of the human mitogen-activated protein kinase p44erk1. Mol. Cell. Biol. 1993;13:4679–4690
  6. Cooper S, Shayman JA. Revisiting retinoblastoma protein phosphorylation during the mammalian cell cycle. Cell. Mol. Life Sci. 2001;58:580–595
  7. Coulonval K, Bockstaele L, Paternot S, Roger PP. Phosphorylations of cyclin-dependent kinase 2 revisited using two-dimensional gel electrophoresis. J. Biol. Chem. 2003;278:52052–52060
  8. Croisier E, Moran LB, Dexter DT, Pearce RKB, Graeber MB. Microglial inflammation in the parkinsonian substantia nigra: relationship to alpha-synuclein deposition. J. Neuroinflam. 2005;2:14
  9. Crystal AS, Giasson BI, Crowe A, Kung M-P, Zhuang Z-P, Trojanowski JQ, et al. A novel assay to monitor amyloidogenicity in solution using the fluorescent dye K114. J. Neurochem. 2003;86:1359–1368
  10. Davidson WS, Jonas A, Clayton DF, George JM. Stabilization of α-synuclein secondary structure upon binding to synthetic membranes. J. Biol. Chem. 1998;273:9443–9449
  11. de Groot CJA, Montagne L, Janssen I, Ravid R, Van Der Valk P, Veerhuis R. Isolation and characterization of adult microglial cells and oligodendrocytes derived from postmortem human brain tissue.. Brain Res. Protocols. 2000;5:85–94
  12. de Silva HR, Khan NL, Wood NW. The genetics of Parkinson's disease. Curr. Opin. Genet. Dev. 2000;10:292–298
  13. Decker T, Lohmann-Matthes ML. A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity. J. Immunol. Meth. 1988;15:61–69
  14. Dong C, Davis RJ, Flavell RA. MAP kinases in the immune response. Ann. Rev. Immunol. 2002;20:55–72
  15. El-Agnaf OM, Jakes R, Curran MD, Middleton D, Ingenito R, Bianchi E, et al. Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of beta-sheet and amyloid-like filaments. FEBS Lett. 1998;440:71–75
  16. El-Agnaf OM, Salem SA, 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
  17. Engel K, Ahlers A, Brach MA, Herrmann F, Gaestel M. MAPKAP kinase 2 is activated by heat shock and TNF-alpha: in vivo phosphorylation of small heat shock protein results from stimulation of the MAP kinase cascade. J. Cell Biochem. 1995;57:321–330
  18. Engel K, Schultz H, Martin F, Kotlyarov A, Plath K, Hahn M, et al. Constitutive activation of mitogen-activated protein kinase-activated protein kinase 2 by mutation of phosphorylation sites and an A-helix motif. J. Biol. Chem. 1995;270:27213–27221
  19. Erikson E, Maller JL. In vivo phosphorylation and activation of ribosomal protein S6 kinases during Xenopus oocyte maturation. J. Biol. Chem. 1989;264:13711–13717
  20. Ferrer I, Blanco R, Carmona M, Puig B, Barrachina M, Gomez C, et al. Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson's disease and Dementia with Lewy bodies. J. Neural Transm. 2001;108:1383–1396
  21. Flynn P, Mellor H, Casamassima A, Parker PJ. Rho GTPase control of protein kinase C-related protein kinase activation by 3-phosphoinositide-dependent protein kinase. J. Biol. Chem. 2000;275:11064–11070
  22. Frasier M, Walzer M, McCarthy L, Magnuson D, Lee JM, Haas C, et al. Tau phosphorylation increases in symptomatic mice overexpressing A30P α-synuclein. Exp. Neurol. 2005;192:274–287
  23. Freshney NW, Rawlinson L, Guesdon F, Jones E, Cowley S, Hsuan J, et al. Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell. 1994;78:1039–1049
  24. Fujita N, Sato S, Katayama K, Tsuruo T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J. Biol. Chem. 2002;277:28706–28713
  25. Gasser T. Genetics of Parkinson's disease. Curr. Opin. Neurol. 2005;18:363–369
  26. George, J.M., 2002. The synucleins. Genome Biol. 3:reviews3002.1-reviews.6.
  27. Giasson BI, Murray IV, Trojanowski JQ, Lee VMY. A hydrophobic stretch of 12 amino acid residues in the middle of alpha-synuclein is essential for filament assembly. J. Biol. Chem. 2001;276:2380–2386
  28. Giasson BI, Uryu K, Trojanowski JQ, Lee VM-Y. Mutant and wild type human α-synucleins assemble into elongated filaments with distinct morphologies in vitro. J. Biol. Chem. 1999;274:7619–7622
  29. Goedert M. Alpha-synuclein and neurodegenerative diseases. Nat. Rev. Neurosci. 2001;2:492–501
  30. Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, et al. The E46K mutation in alpha-synuclein increases amyloid fibril formation. J. Biol. Chem. 2005;280:7800–7807
  31. Grove JR, Price DJ, Banerjee P, Balasubramanyam A, Ahmad MF, Avruch J. Regulation of an epitope-tagged recombinant Rsk-1 S6 kinase by phorbol ester and erk/MAP kinase. Biochemistry. 1993;32:7727–7738
  32. Hansen MB, Nielsen SE, Berg K. Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J. Immunol. Meth. 1989;119:203–210
  33. Hashimoto M, Hsu LJ, Rockenstein E, Takenouchi T, Mallory M, Masliah E. α-Synuclein protects against oxidative stress via inactivation of the c-Jun N-terminal kinase stress-signaling pathway in neuronal cells. J. Biol. Chem. 2002;277:11465–11472
  34. Hide I, Tanaka M, Inoue A, Nakajima K, Kohsaka S, Inoue K, et al. Extracellular ATP triggers tumor necrosis factor-alpha release from rat microglia. J. Neurochem. 2000;75:965–972
  35. Horvath CM, Darnell JE. The state of the STATs: recent developments in the study of signal transduction to the nucleus. Curr. Opin. Cell Biol. 1997;9:233–239
  36. Huang B, Porter G. Expression of proline-rich Akt-substrate PRAS40 in cell survival pathway and carcinogenesis. Acta Pharmacol. Sin. 2005;26:1253–1258
  37. Iseki E, Marui W, Akiyama H, Ueda K, Kosaka K. Degeneration process of Lewy bodies in the brains of patients with dementia with Lewy bodies using α-synuclein-immunohistochemistry. Neurosci. Lett. 2000;286:69–73
  38. Ishizawa K, Komori T, Sasaki S, Arai N, Mizutani T, Hirose T. Microglial activation parallels system degeneration in multiple system atrophy. J. Neuropath. Exp. Neurol. 2004;63:43–52
  39. Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, et al. The precursor protein of non-Aβ component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron. 1995;14:467–475
  40. Iwata A, Maruyama M, Kanazawa I, Nukina N. α-Synuclein affects the MAPK pathway and accelerates cell death. J. Biol. Chem. 2001;276:45320–45329
  41. Jensen CJ, Buch MB, Krag TO, Hemmings BA, Gammeltoft S, Frodin M. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. J. Biol. Chem. 1999;274:27168–27176
  42. Kim YS, Kim SS, Cho JJ, Choi DH, Hwang O, Shin DH, et al. Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. J. Neurosci. 2005;25:3701–3711
  43. Kitagawa M, Higashi H, Jung HK, Suzuki-Takahashi I, Ikeda M, Tamai K, et al. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J. 1996;15:7060–7069
  44. Klegeris A, Bissonnette CJ, McGeer PL. Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid type CB2 receptor. Br. J. Pharmacol. 2003;139:775–786
  45. Klegeris A, Giasson BI, Zhang H, Maguire J, Pelech S, McGeer PL. Alpha-synuclein and its disease-causing mutants induce ICAM-1 and IL-6 in astrocytes and astrocytoma cells. FASEB J. 2006;20:2000–2008
  46. Klegeris A, McGeer PL. Chymotrypsin-like proteases contribute to human monocytic THP-1 cell as well as human microglial neurotoxicity. Glia. 2005;51:56–64
  47. Klegeris A, McGeer PL. Interaction of various intracellular signaling mechanisms involved in mononuclear phagocyte toxicity toward neuronal cells. J. Leukoc. Biol. 2000;67:127–133
  48. Knudsen ES, Wang JY. Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites. J. Biol. Chem. 1996;271:8313–8320
  49. 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;18:106–108
  50. Lee HJ, Patel S, Lee SJ. Intravesicular localization and exocytosis of α-synuclein and its aggregates. J. Neurosci. 2005;25:6016–6024
  51. Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ. A precipitating role for truncated α-synuclein and the proteasome in α-synuclein aggregation: implications for pathogenesis of Parkinson disease. J. Biol. Chem. 2005;280:22670–22678
  52. McDonald DR, Bamberger ME, Combs CK, Landreth GE. β-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. J. Neurosci. 1998;18:4451–4460
  53. Minden A, Lin A, Smeal T, Derijard B, Cobb M, Davis R, et al. c-Jun N-terminal phosphorylation correlates with activation of the JNK subgroup but not the ERK subgroup of mitogen-activated protein kinases. Mol. Cell Biol. 1994;14:6683–6688
  54. Mishizen-Eberz AJ, Guttmann RP, Giasson BI, Day GA, Hodara R, Ischiropoulos H, et al. Distinct cleavage patterns of normal and pathologic forms of α-synuclein by calpain I in vitro. J. Neurochem. 2003;86:836–847
  55. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Meth. 1983;65:55–63
  56. Murray IVJ, Giasson BI, Quinn SM, Koppaka V, Axelsen PH, Ischiropoulos H, et al. The role of the carboxy terminus of alpha-synuclein on fibril formation in vitro. Biochemistry. 2003;42:8530–8540
  57. Nakajo S, Shioda S, Nakai Y, Nakaya K. Localization of phosphoneuroprotein 14 (PNP 14) and its mRNA expression in rat brain determined by immunocytochemistry and in situ hybridization. Brain Res. Mol. Brain Res. 1994;27:81–86
  58. Nave BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 1999;344:427–431
  59. Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, Imai H, et al. Clinical heterogeneity of α-synuclein gene duplication in Parkinson's disease. Ann. Neurol. 2006;59:298–309
  60. Norris EH, Giasson BI, Lee VM. Alpha-synuclein: normal function and role in neurodegenerative diseases. Curr. Topics Dev. Biol. 2004;60:17–54
  61. Pelech S, Sutter C, Zhang H. Kinetworks protein kinase multiblot analysis. Meth. Mol. Biol. 2003;218:99–111
  62. Perez RG, Hastings TG. Could a loss of alpha-synuclein function put dopaminergic neurons at risk?. J. Neurochem. 2004;89:1318–1324
  63. 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;276:2045–2047
  64. Seo JH, Rah JC, Choi SH, Shin JK, Min K, Kim HS, et al. α-Synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. FASEB J. 2002;16:1826–1828
  65. Siow YL, Kalmar GB, Sanghera JS, Tai G, Oh SS, Pelech SL. Identification of two essential phosphorylated threonine residues in the catalytic domain of Mekk1. Indirect activation by Pak3 and protein kinase C. J. Biol. Chem. 1997;272:7586–7594
  66. Souza JM, Giasson BI, Chen Q, Lee VM, Ischiropoulos H. Dityrosine cross-linking promotes formation of stable α-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J. Biol. Chem. 2000;275:18344–18349
  67. Stefanova N, Reindl M, Neumann M, Haass C, Poewe W, Kahle PJ, et al. Oxidative stress in transgenic mice with oligodendroglial α-synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am. J. Pathol. 2005;166:869–876
  68. Sung JY, Park SM, Lee CH, Um JW, Lee HJ, Kim J, et al. Proteolytic cleavage of extracellular secreted α-synuclein via matrix metalloproteinases. J. Biol. Chem. 2005;280:25216–25224
  69. Sutherland C, Leighton IA, Cohen P. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem. J. 1993;296:15–19
  70. Takahashi-Yanaga F, Shiraishi F, Hirata M, Miwa Y, Morimoto S, Sasaguri T. Glycogen synthase kinase-3beta is tyrosine-phosphorylated by MEK1 in human skin fibroblasts. Biochem. Biophys. Res. Commun. 2004;316:411–415
  71. Tarapore P, Shinmura K, Suzuki H, Tokuyama Y, Kim SH, Mayeda A, et al. Thr199 phosphorylation targets nucleophosmin to nuclear speckles and represses pre-mRNA processing. FEBS Lett. 2006;580:399–409
  72. Vik TA, Ryder JW. Identification of serine 380 as the major site of autophosphorylation of Xenopus pp90rsk. Biochem. Biophys. Res. Commun. 1997;235:398–402
  73. Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry. 1996;35:13709–13715
  74. Wick MJ, Dong LQ, Riojas RA, Ramos FJ, Liu F. Mechanism of phosphorylation of protein kinase B/Akt by a constitutively active 3-phosphoinositide-dependent protein kinase-1. J. Biol. Chem. 2000;275:40400–40406
  75. Xing J, Kornhauser JM, Xia Z, Thiele EA, Greenberg ME. Nerve growth factor activates extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways to stimulate CREB serine 133 phosphorylation. Mol. Cell Biol. 1998;18:1946–1955
  76. Xu B, Wilsbacher JL, Collisson T, Cobb MH. The N-terminal ERK-binding site of MEK1 is required for efficient feedback phosphorylation by ERK2 in vitro and ERK activation in vivo. J. Biol. Chem. 1999;274:34029–34035
  77. Zarranz JJ, Alegre J, Gomez-Estaban 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;55:164–173
  78. Zhang H, Shi X, Paddon H, Hampong M, Dai W, Pelech S. B23/nucleophosmin serine 4 phosphorylation mediates mitotic functions of polo-like kinase 1. J. Biol. Chem. 2004;279:35726–35734
  79. Zhang H, Shi X, Zhang QJ, Hampong M, Paddon H, Wahyuningsih D, et al. Nocodazole-induced p53-dependent c-Jun N-terminal kinase activation reduces apoptosis in human colon carcinoma HCT116 cells. J. Biol. Chem. 2002;277:43648–43658
  80. Zhang W, Wang T, Pei Z, Miller DS, Wu X, Block ML, et al. α-synuclein activates microglia: a process leading to disease progression in Parkinson's disease. FASEB J. 2005;19:533–542
  81. Zheng CF, Guan KL. Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues. EMBO J. 1994;13:1123–1131
  82. Zhu JH, Guo F, Shelburne J, Watkins S, Chu CT. Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol. 2003;13:473–481
  83. Zhu JH, Kulich SM, Oury TD, Chu CT. Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. Am. J. Pathol. 2002;161:2087–2098

PII: S0197-4580(06)00436-2

doi: 10.1016/j.neurobiolaging.2006.11.013

Neurobiology of Aging
Volume 29, Issue 5 , Pages 739-752 , May 2008