Journal of Neural Transmission

, Volume 118, Issue 3, pp 421–431 | Cite as

Iron mediates neuritic tree collapse in mesencephalic neurons treated with 1-methyl-4-phenylpyridinium (MPP+)

  • Francisco J. Gómez
  • Pabla Aguirre
  • Christian Gonzalez-Billault
  • Marco T. Núñez
Basic Neurosciences, Genetics and Immunology - Original Article
First Online:
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Accepted:

Abstract

Studies in post-mortem tissues of patients with Parkinson’s disease (PD) and in mice treated with 6-hydroxydopamine have shown a decrease in the length of axon and dendrites of striatal neurons. However, the etiology of the morphological changes and their relationship to inhibition of mitochondrial complex I and the cellular levels of iron and glutathione (GSH) have not been described. In this study, we characterized the effect of MPP+, an inhibitor of mitochondria complex I, on the integrity of the neuritic tree of midbrain dopaminergic neurons, and determined the influence of iron and cellular levels of GSH on this degeneration. Sub-maximal concentrations of MPP+ induced a drastic dose-dependent reduction of neurites, without modification of the soma or apparent cell death. Concurrent treatment with MPP+ and non-toxic concentrations of iron accelerated the process of degeneration, whereas neurons grown on a medium low in iron showed enhanced resistance to MPP+ treatment. MPP+-induced neurite shortening depended on the redox state of neurons. Pre-treatment with the general antioxidant N-acetyl cysteine protected neurons from degeneration. Treatment with sub-maximal concentrations of the inhibitor of GSH synthesis buthionine sulfoximine (BSO), in conjunction with iron and MPP+, produced massive cell death, whereas treatment with BSO plus MPP+ under low iron conditions did not damage neurons. These results suggest that under conditions of inhibition of mitochondrial complex I caused by MPP+, the accumulation of iron and the concurrent decrease in GSH results in the loss of the dendritic tree prior to cell death, of dopaminergic neurons in PD.

Keywords

Iron Parkinson Glutathione Complex I Antioxidants 
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Notes

Acknowledgments

This work was financed by Grant 1100599 from Fondo Nacional de Ciencia y Tecnología Chile, (FONDECYT) and by project ICM-P05-001-F from the Millennium Scientific Initiative, Ministerio de Planificación Nacional (MIDEPLAN).

References

  1. Arredondo M, Martinez R, Núñez MT, Ruz M, Olivares M (2006) Inhibition of iron and copper uptake by iron, copper and zinc. Biol Res 39(1):95–102PubMedCrossRefGoogle Scholar
  2. Baloyannis SJ (2009) Dendritic pathology in Alzheimer’s disease. J Neurol Sci 283(1–2):153–157PubMedCrossRefGoogle Scholar
  3. Baloyannis SJ, Costa V, Baloyannis IS (2006) Morphological alterations of the synapses in the locus coeruleus in Parkinson’s disease. J Neurol Sci 248(1–2):35–41PubMedCrossRefGoogle Scholar
  4. Banerjee R, Starkov AA, Beal MF, Thomas B (2009) Mitochondrial dysfunction in the limelight of Parkinson’s disease pathogenesis. Biochim Biophys Acta 1792(7):651–663PubMedGoogle Scholar
  5. Berg D, Youdim MB (2006) Role of iron in neurodegenerative disorders. Top Magn Reson Imaging 17(1):5–17PubMedCrossRefGoogle Scholar
  6. Borquez D, Valdés P, Núñez MT (2008) Iron toxicity: a critical review on its role in Parkinson’s disease. In: Von Bernhardi R, Inestrosa NC (eds) Neurodegenerative diseases: from molecular concepts to therapeutic targets. Nova Science Publishers, Inc., Hauppauge, New York, pp 189–204Google Scholar
  7. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nat Med 10(Suppl):S2–S9PubMedCrossRefGoogle Scholar
  8. Brouard A, Pelaprat D, Dana C, Vial M, Lhiaubet AM, Rostene W (1992) Mesencephalic dopaminergic neurons in primary cultures express functional neurotensin receptors. J Neurosci 12(4):1409–1415PubMedGoogle Scholar
  9. Capetillo-Zarate E, Staufenbiel M, Abramowski D, Haass C, Escher A, Stadelmann C, Yamaguchi H, Wiestler OD, Thal DR (2006) Selective vulnerability of different types of commissural neurons for amyloid beta-protein-induced neurodegeneration in APP23 mice correlates with dendritic tree morphology. Brain 129(Pt 11):2992–3005PubMedCrossRefGoogle Scholar
  10. Chinta SJ, Kumar JM, Zhang H, Forman HJ, Andersen JK (2006) Up-regulation of gamma-glutamyl transpeptidase activity following glutathione depletion has a compensatory rather than an inhibitory effect on mitochondrial complex I activity: implications for Parkinson’s disease. Free Radic Biol Med 40(9):1557–1563PubMedCrossRefGoogle Scholar
  11. Cleeter MWJ, Schapira AH (1992) Irreversible inhibition of mitochondrial complex I by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: evidence for free radical involvement. J Neurochem 58(2):786–789PubMedCrossRefGoogle Scholar
  12. Coleman M (2005) Axon degeneration mechanisms: commonality amid diversity. Nat Rev Neurosci 6(11):889–898PubMedCrossRefGoogle Scholar
  13. Coombs JL, Van Der List D, Chalupa LM (2007) Morphological properties of mouse retinal ganglion cells during postnatal development. J Comp Neurol 503(6):803–814PubMedCrossRefGoogle Scholar
  14. D’Alessio M, Cerella C, Amici C, Pesce C, Coppola S, Fanelli C, De Nicola M, Cristofanon S, Clavarino G, Bergamaschi A, Magrini A, Gualandi G, Ghibelli L (2004) Glutathione depletion up-regulates Bcl-2 in BSO-resistant cells. Faseb J 18(13):1609–1611PubMedGoogle Scholar
  15. Del Zompo MPM, Ruiu S, Quartu M, Gessa GL, Vaccari A (1993) Selective uptake into synaptic dopamine vesicles: possible involvement in MPTP neurotoxicity. Br J Pharmacol 109(2):411–414PubMedGoogle Scholar
  16. Engele J, Rieck H, Choi-Lundberg D, Bohn MC (1996) Evidence for a novel neurotrophic factor for dopaminergic neurons secreted from mesencephalic glial cell lines. J Neurosci Res 43(5):576–586PubMedCrossRefGoogle Scholar
  17. Fiala JC, Spacek J, Harris KM (2002) Dendritic spine pathology: cause or consequence of neurological disorders? Brain Res Brain Res Rev 39(1):29–54PubMedCrossRefGoogle Scholar
  18. Fitzmaurice PS, Ang L, Guttman M, Rajput AH, Furukawa Y, Kish SJ (2003) Nigral glutathione deficiency is not specific for idiopathic Parkinson’s disease. Mov Disord 18(9):969–976PubMedCrossRefGoogle Scholar
  19. Gulledge AT, Kampa BM, Stuart GJ (2005) Synaptic integration in dendritic trees. J Neurobiol 64(1):75–90PubMedCrossRefGoogle Scholar
  20. Halliwell B (2006) Reactive species and antioxidants Redox biology is a fundamental theme of aerobic life. Plant Physiol 141(2):312–322PubMedCrossRefGoogle Scholar
  21. Hattingen E, Magerkurth J, Pilatus U, Mozer A, Seifried C, Steinmetz H, Zanella F, Hilker R (2009) Phosphorus and proton magnetic resonance spectroscopy demonstrates mitochondrial dysfunction in early and advanced Parkinson’s disease. Brain 132(Pt 12):3285–3297PubMedCrossRefGoogle Scholar
  22. Jenner P, Olanow CW (1998) Understanding cell death in Parkinson’s disease. Ann Neurol 44(3 Suppl 1):S72–S84PubMedGoogle Scholar
  23. Jenner P, Olanow CW (2006) The pathogenesis of cell death in Parkinson’s disease. Neurology 66(10 Suppl 4):S24–S36PubMedGoogle Scholar
  24. Johnston D, Magee JC, Colbert CM, Cristie BR (1996) Active properties of neuronal dendrites. Annu Rev Neurosci 19:165–186PubMedCrossRefGoogle Scholar
  25. Kalivendi SV, Kotamraju S, Cunningham S, Shang T, Hillard CJ, Kalyanaraman B (2003) 1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. Biochem J 371(Pt 1):151–164PubMedCrossRefGoogle Scholar
  26. Kienzl E, Jellinger K, Stachelberger H, Linert W (1999) Iron as catalyst for oxidative stress in the pathogenesis of Parkinson’s disease? Life Sci 65(18–19):1973–1976PubMedCrossRefGoogle Scholar
  27. Mandel SA, Fishman T, Youdim MB (2007) Gene and protein signatures in sporadic Parkinson’s disease and a novel genetic model of PD. Parkinsonism Relat Disord 13(Suppl 3):S242–S247PubMedCrossRefGoogle Scholar
  28. Mayer RA, Kindt MV, Heikkila RE (1986) Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport. J Neurochem 47(4):1073–1079PubMedCrossRefGoogle Scholar
  29. McNeill TH, Brown SA, Rafols JA, Shoulson I (1988) Atrophy of medium spiny I striatal dendrites in advanced Parkinson’s disease. Brain Res 455(1):148–152PubMedCrossRefGoogle Scholar
  30. Meister A, Anderson ME (1983) Glutathione. Annu Rev Biochem 52:711–760PubMedCrossRefGoogle Scholar
  31. Mena NP, Esparza A, Tapia V, Valdes P, Núñez MT (2008) Hepcidin inhibits apical iron uptake in intestinal cells. Am J Physiol Gastrointest Liver Physiol 294(1):G192–G198PubMedCrossRefGoogle Scholar
  32. Morfini G, Pigino G, Opalach K, Serulle Y, Moreira JE, Sugimori M, Llinas RR, Brady ST (2007) 1-Methyl-4-phenylpyridinium affects fast axonal transport by activation of caspase and protein kinase C. Proc Natl Acad Sci USA 104(7):2442–2447PubMedCrossRefGoogle Scholar
  33. Nicklas WJ, Youngster SK, Kindt MV, Heikkila RE (1987) MPTP, MPP+ and mitochondrial function. Life Sci 40(8):721–729PubMedCrossRefGoogle Scholar
  34. Núñez MT, Tapia V (1999) Transferrin stimulates iron absorption, exocytosis, and secretion in cultured intestinal cells. Am J Physiol 276(5 Pt 1):C1085–C1090PubMedGoogle Scholar
  35. Núñez MT, Gallardo V, Muñoz P, Tapia V, Esparza A, Salazar J, Speisky H (2004) Progressive iron accumulation induces a biphasic change in the glutathione content of neuroblastoma cells. Free Radic Biol Med 37(7):953–960PubMedCrossRefGoogle Scholar
  36. Paris I, Martinez-Alvarado P, Cardenas S, Perez-Pastene C, Graumann R, Fuentes P, Olea-Azar C, Caviedes P, Segura-Aguilar J (2005) Dopamine-dependent iron toxicity in cells derived from rat hypothalamus. Chem Res Toxicol 18(3):415–419PubMedCrossRefGoogle Scholar
  37. Perry TL, Godin DV, Hansen S (1982) Parkinson’s disease: a disorder due to nigral glutathione deficiency? Neurosci Lett 33(3):305–310PubMedCrossRefGoogle Scholar
  38. Perry G, Taddeo MA, Petersen RB, Castellani RJ, Harris PL, Siedlak SL, Cash AD, Liu Q, Nunomura A, Atwood CS, Smith MA (2003) Adventiously-bound redox active iron and copper are at the center of oxidative damage in Alzheimer disease. Biometals 16(1):77–81PubMedCrossRefGoogle Scholar
  39. Przedborski S, Vila M (2003) The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model: a tool to explore the pathogenesis of Parkinson’s disease. Ann N Y Acad Sci 991:189–198PubMedCrossRefGoogle Scholar
  40. Sayre LM, Perry G, Atwood CS, Smith MA (2000) The role of metals in neurodegenerative diseases. Cell Mol Biol (Noisy-le-grand) 46(4):731–741Google Scholar
  41. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 54(3):823–827PubMedCrossRefGoogle Scholar
  42. Scotcher KP, Irwin I, DeLanney LE, Langston JW, Di Monte D (1990) Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenylpyridinium ion on ATP levels of mouse brain synaptosomes. J Neurochem 54(4):1295–1301PubMedCrossRefGoogle Scholar
  43. Sian J, Dexter DT, Lees AJ, Daniel S, Agid Y, Javoy-Agid F, Jenner P, Marsden CD (1994) Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Ann Neurol 36(3):348–355PubMedCrossRefGoogle Scholar
  44. Smeyne RJ, Jackson-Lewis V (2005) The MPTP model of Parkinson’s disease. Brain Res Mol Brain Res 134(1):57–66PubMedCrossRefGoogle Scholar
  45. Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MB (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74(3):199–205PubMedCrossRefGoogle Scholar
  46. Solis O, Limon DI, Flores-Hernandez J, Flores G (2007) Alterations in dendritic morphology of the prefrontal cortical and striatum neurons in the unilateral 6-OHDA-rat model of Parkinson’s disease. Synapse 61(6):450–458PubMedCrossRefGoogle Scholar
  47. Stephens B, Mueller AJ, Shering AF, Hood SH, Taggart P, Arbuthnott GW, Bell JE, Kilford L, Kingsbury AE, Daniel SE, Ingham CA (2005) Evidence of a breakdown of corticostriatal connections in Parkinson’s disease. Neuroscience 132(3):741–754PubMedCrossRefGoogle Scholar
  48. Suzumura A, Takeuchi H, Zhang G, Kuno R, Mizuno T (2006) Roles of glia-derived cytokines on neuronal degeneration and regeneration. Ann N Y Acad Sci 1088:219–229PubMedCrossRefGoogle Scholar
  49. Takeuchi H, Mizuno T, Zhang G, Wang J, Kawanokuchi J, Kuno R, Suzumura A (2005) Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J Biol Chem 280(11):10444–10454PubMedCrossRefGoogle Scholar
  50. Vali S, Mythri RB, Jagatha B, Padiadpu J, Ramanujan KS, Andersen JK, Gorin F, Bharath MM (2007) Integrating glutathione metabolism and mitochondrial dysfunction with implications for Parkinson’s disease: a dynamic model. Neuroscience 149(4):917–930PubMedCrossRefGoogle Scholar
  51. Vetter P, Roth A, Hausser M (2001) Propagation of action potentials in dendrites depends on dendritic morphology. J Neurophysiol 85(2):926–937PubMedGoogle Scholar
  52. Weinreb O, Amit T, Mandel SA, Kupershmidt L, Youdim MB (2010) Neuroprotective multifunctional iron chelators: from redox-sensitive process to novel therapeutic opportunities. Antioxid Redox Signal 13(6):919–949Google Scholar
  53. Wong SS, Li RH, Stadlin A (1999) Oxidative stress induced by MPTP and MPP(+): selective vulnerability of cultured mouse astrocytes. Brain Res 836(1–2):237–244PubMedCrossRefGoogle Scholar
  54. Youdim MB (2008) Brain iron deficiency and excess; cognitive impairment and neurodegeneration with involvement of striatum and hippocampus. Neurotox Res 14(1):45–56PubMedCrossRefGoogle Scholar
  55. Youdim MB, Riederer P (1997) Understanding Parkinson’s disease. Sci Am 276(1):52–59PubMedCrossRefGoogle Scholar
  56. Zaja-Milatovic S, Milatovic D, Schantz AM, Zhang J, Montine KS, Samii A, Deutch AY, Montine TJ (2005) Dendritic degeneration in neostriatal medium spiny neurons in Parkinson disease. Neurology 64(3):545–547PubMedGoogle Scholar
  57. Zoccarato F, Toscano P, Alexandre A (2005) Dopamine-derived dopaminochrome promotes H(2)O(2) release at mitochondrial complex I: stimulation by rotenone, control by Ca(2+), and relevance to Parkinson disease. J Biol Chem 280(16):15587–15594PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Francisco J. Gómez
    • 1
  • Pabla Aguirre
    • 1
  • Christian Gonzalez-Billault
    • 1
  • Marco T. Núñez
    • 1
    • 2
  1. 1.Department of Biology, Faculty of Sciences, Cell Dynamics and Biotechnology InstituteUniversidad de ChileSantiagoChile
  2. 2.Departamento de Biología, Facultad de CienciasUniversidad de ChileSantiagoChile

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