Abstract
Peroxiredoxin 6 (PRDX6) is a bifunctional protein with both glutathione peroxidase (GPx) and calcium-independent phospholipase A2 (iPLA2) activities. Expression of PRDX6 has been detected in human Parkinson’s disease (PD) and dementia patients. However, no study has described PRDX6 function in the dopaminergic neurodegeneration in PD. Herein, we investigated the effects of PRDX6 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration using PRDX6 transgenic (Tg) mice. Immunohistochemistry (IHC) and Western blot data for tyrosine hydroxylase (TH) showed that PRDX6 Tg mice had much higher loss of dopaminergic neurons by MPTP administration compared to non-Tg mice, as well as there was much higher behavioral impairment and astrocyte activation in PRDX6 Tg mice. MPTP-induced GPx activity was not different between PRDX6 Tg mice and non-Tg mice, which is accompanied by hyperoxidation of PRDX6. While iPLA2 activity was increased in PRDX6 Tg mice followed by an increase in the level of ROS and 4-hydroxynonenal (4-HNE). Intriguingly, the expression pattern of PRDX6 showed similar distribution and co-localization with astrocytes, but not neuron in the mouse and human brain. Furthermore, we demonstrated that iPLA2 activity of PRDX6 induced astrocytic activation followed by increased proinflammatory cytokines (TNF-α and IL1-β), 4-HNE, and PRDX6 hyperoxidation in primary cultured astrocytes. Our findings provide novel insights for PRDX6 function on nigrostriatal dopaminergic neuronal system, and we suggest that PRDX6 has an important role in dopaminergic neurodegeneration of PD.
Similar content being viewed by others
References
Blesa J, Phani S, Jackson-Lewis V, Przedborski S (2012) Classic and new animal models of Parkinson’s disease. J Biomed Biotechnol 2012:845618. doi:10.1155/2012/845618
Blandini F, Nappi G, Tassorelli C, Martignoni E (2000) Functional changes of the basal ganglia circuitry in Parkinson’s disease. Prog Neurobiol 62(1):63–88
Graybiel AM (1990) The basal ganglia and the initiation of movement. Rev Neurol (Paris) 146(10):570–574
Hirsch EC, Breidert T, Rousselet E, Hunot S, Hartmann A, Michel PP (2003) The role of glial reaction and inflammation in Parkinson’s disease. Ann N Y Acad Sci 991:214–228
Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219(4587):979–980
Bove J, Zhou C, Jackson-Lewis V, Taylor J, Chu Y, Rideout HJ, Wu DC, Kordower JH, Petrucelli L, Przedborski S (2006) Proteasome inhibition and Parkinson’s disease modeling. Ann Neurol 60(2):260–264. doi:10.1002/ana.20937
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39(6):889–909
Exner N, Lutz AK, Haass C, Winklhofer KF (2012) Mitochondrial dysfunction in Parkinson’s disease: molecular mechanisms and pathophysiological consequences. EMBO J 31(14):3038–3062. doi:10.1038/emboj.2012.170
Jackson-Lewis V, Przedborski S (2007) Protocol for the MPTP mouse model of Parkinson’s disease. Nat Protoc 2(1):141–151. doi:10.1038/nprot.2006.342
Jenner P, Olanow CW (1996) Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 47(6 Suppl 3):S161–170
Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443(7113):787–795. doi:10.1038/nature05292
Ghosh A, Kanthasamy A, Joseph J, Anantharam V, Srivastava P, Dranka BP, Kalyanaraman B, Kanthasamy AG (2012) Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease. J Neuroinflammation 9:241. doi:10.1186/1742-2094-9-241
Rappold PM, Tieu K (2010) Astrocytes and therapeutics for Parkinson’s disease. Neurotherapeutics 7(4):413–423. doi:10.1016/j.nurt.2010.07.001
Andreoletti O, Levavasseur E, Uro-Coste E, Tabouret G, Sarradin P, Delisle MB, Berthon P, Salvayre R, Schelcher F, Negre-Salvayre A (2002) Astrocytes accumulate 4-hydroxynonenal adducts in murine scrapie and human Creutzfeldt-Jakob disease. Neurobiol Dis 11(3):386–393
Farooqui AA, Horrocks LA (2006) Phospholipase A2-generated lipid mediators in the brain: the good, the bad, and the ugly. Neuroscientist 12(3):245–260. doi:10.1177/1073858405285923
Teismann P, Schulz JB (2004) Cellular pathology of Parkinson’s disease: astrocytes, microglia and inflammation. Cell Tissue Res 318(1):149–161. doi:10.1007/s00441-004-0944-0
Yun HM, Jin P, Han JY, Lee MS, Han SB, Oh KW, Hong SH, Jung EY, Hong JT (2013) Acceleration of the development of Alzheimer’s disease in amyloid beta-infused peroxiredoxin 6 overexpression transgenic mice. Mol Neurobiol 48(3):941–951. doi:10.1007/s12035-013-8479-6
Chae HZ, Chung SJ, Rhee SG (1994) Thioredoxin-dependent peroxide reductase from yeast. J Biol Chem 269(44):27670–27678
Wood ZA, Schroder E, Robin Harris J, Poole LB (2003) Structure, mechanism and regulation of peroxiredoxins. Trends Biochem Sci 28(1):32–40
Wang Y, Feinstein SI, Fisher AB (2008) Peroxiredoxin 6 as an antioxidant enzyme: protection of lung alveolar epithelial type II cells from H2O2-induced oxidative stress. J Cell Biochem 104(4):1274–1285. doi:10.1002/jcb.21703
Rahaman H, Zhou S, Dodia C, Feinstein SI, Huang S, Speicher D, Fisher AB (2012) Increased phospholipase A2 activity with phosphorylation of peroxiredoxin 6 requires a conformational change in the protein. Biochemistry 51(27):5521–5530. doi:10.1021/bi300380h
Chen JW, Dodia C, Feinstein SI, Jain MK, Fisher AB (2000) 1-Cys peroxiredoxin, a bifunctional enzyme with glutathione peroxidase and phospholipase A2 activities. J Biol Chem 275(37):28421–28427. doi:10.1074/jbc.M005073200
Chatterjee S, Feinstein SI, Dodia C, Sorokina E, Lien YC, Nguyen S, Debolt K, Speicher D, Fisher AB (2011) Peroxiredoxin 6 phosphorylation and subsequent phospholipase A2 activity are required for agonist-mediated activation of NADPH oxidase in mouse pulmonary microvascular endothelium and alveolar macrophages. J Biol Chem 286(13):11696–11706. doi:10.1074/jbc.M110.206623
Krishnaiah SY, Dodia C, Feinstein SI, Fisher AB (2013) p67(phox) terminates the phospholipase A(2)-derived signal for activation of NADPH oxidase (NOX2). FASEB J 27(5):2066–2073. doi:10.1096/fj.12-222133
Kim SY, Jo HY, Kim MH, Cha YY, Choi SW, Shim JH, Kim TJ, Lee KY (2008) H2O2-dependent hyperoxidation of peroxiredoxin 6 (Prdx6) plays a role in cellular toxicity via up-regulation of iPLA2 activity. J Biol Chem 283(48):33563–33568. doi:10.1074/jbc.M806578200
Kwon HS, Bae YJ, Moon KA, Lee YS, Lee T, Lee KY, Kim TB, Park CS, Moon HB, Cho YS (2012) Hyperoxidized peroxiredoxins in peripheral blood mononuclear cells of asthma patients is associated with asthma severity. Life Sci 90(13–14):502–508. doi:10.1016/j.lfs.2012.01.003
Kim SY, Chun E, Lee KY (2011) Phospholipase A(2) of peroxiredoxin 6 has a critical role in tumor necrosis factor-induced apoptosis. Cell Death Differ 18(10):1573–1583. doi:10.1038/cdd.2011.21
Jin MH, Lee YH, Kim JM, Sun HN, Moon EY, Shong MH, Kim SU, Lee SH, Lee TH, Yu DY, Lee DS (2005) Characterization of neural cell types expressing peroxiredoxins in mouse brain. Neurosci Lett 381(3):252–257. doi:10.1016/j.neulet.2005.02.048
Power JH, Shannon JM, Blumbergs PC, Gai WP (2002) Nonselenium glutathione peroxidase in human brain : elevated levels in Parkinson’s disease and dementia with lewy bodies. Am J Pathol 161(3):885–894. doi:10.1016/S0002-9440(10)64249-6
Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2(12):679–689. doi:10.1038/ncpneuro0355
Sun GY, Xu J, Jensen MD, Simonyi A (2004) Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases. J Lipid Res 45(2):205–213. doi:10.1194/jlr.R300016-JLR200
Fiebich BL, Hull M, Lieb K, Gyufko K, Berger M, Bauer J (1997) Prostaglandin E2 induces interleukin-6 synthesis in human astrocytoma cells. J Neurochem 68(2):704–709
Keller JN, Mattson MP (1998) Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system. Rev Neurosci 9(2):105–116
Tariq M, Khan HA, Al Moutaery K, Al Deeb S (2001) Protective effect of quinacrine on striatal dopamine levels in 6-OHDA and MPTP models of Parkinsonism in rodents. Brain Res Bull 54(1):77–82
Klivenyi P, Beal MF, Ferrante RJ, Andreassen OA, Wermer M, Chin MR, Bonventre JV (1998) Mice deficient in group IV cytosolic phospholipase A2 are resistant to MPTP neurotoxicity. J Neurochem 71(6):2634–2637
Saijo K, Winner B, Carson CT, Collier JG, Boyer L, Rosenfeld MG, Gage FH, Glass CK (2009) A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell 137(1):47–59. doi:10.1016/j.cell.2009.01.038
Power JH, Asad S, Chataway TK, Chegini F, Manavis J, Temlett JA, Jensen PH, Blumbergs PC, Gai WP (2008) Peroxiredoxin 6 in human brain: molecular forms, cellular distribution and association with Alzheimer’s disease pathology. Acta Neuropathol 115(6):611–622. doi:10.1007/s00401-008-0373-3
Xu J, Yu S, Sun AY, Sun GY (2003) Oxidant-mediated AA release from astrocytes involves cPLA(2) and iPLA(2). Free Radic Biol Med 34(12):1531–1543
Acknowledgments
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean Government (MISP) (No. MRC, 2008-0062275), by a grant (A101836) from the Korean Health Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea. We extend our appreciation to Dr. Sanghyeon Kim (Associate Director for database management, SMRI Laboratory of Brain Research, Rockville, MD) for kindly providing the human brain test samples.
Conflict of Interest
The authors declare no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Yun, HM., Choi, D.Y., Oh, K.W. et al. PRDX6 Exacerbates Dopaminergic Neurodegeneration in a MPTP Mouse Model of Parkinson’s Disease. Mol Neurobiol 52, 422–431 (2015). https://doi.org/10.1007/s12035-014-8885-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-014-8885-4