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Glial HO-1 expression, iron deposition and oxidative stress in neurodegenerative diseases

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Abstract

The mechanisms responsible for the pathological deposition of brain iron in Parkinson’s disease, Alzheimer’s disease and other human neurodegenerative disorders remain poorly understood. In rat primary astrocyte cultures, we demonstrated that dopamine, cysteamine, H2O2 and menadione rapidly induce heme oxygenase-1 (HO-1) expression (mRNA and protein) followed by sequestration of non-transferrin-derived55Fe by the mitochondrial compartment. The effects of dopamine on HO-1 expression were inhibited by ascorbate implicating a free radical mechanism of action. Dopamine-induced mitochondrial iron trapping was abrogated by administration of the heme oxygenase inhibitors, tin mesoporphyrin (SnMP) or dexamethasone (DEX) indicating that HO-1 up-regulation is necessary for subsequent mitochondrial iron deposition in these cells. Over-expression of the human HO-1 gene in cultured rat astroglia by transient transfection also stimulated mitochondrial55Fe deposition, an effect that was again preventible by SnMP or DEX administration. We hypothesize that free ferrous iron and carbon monoxide generated by HO-1-mediated heme degradation promote mitochondrial membrane injury and the deposition of redox-active iron within this organelle. We have shown that the percentages of GFAP-positive astrocytes that co-express HO-1 in Parkinson-affected substantia nigra and Alzheimer-diseased hippocampus are significantly increased relative to age-matched controls. Stress-induced up-regulation of HO-1 in astroglia may be responsible for the abnormal patterns of brain iron deposition and mitochondrial insufficiency documented in various human neurodegenerative disorders.

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References

  • Applegate, L.A., Luscher, P. and Tyrrell, R.M. (1991) Induction of heme oxygenase: a general response to oxidant stress in cultured mammalian cells.Cancer Res. 51, 974–978.

    PubMed  CAS  Google Scholar 

  • Chopra, VS., Chalifour, L.E. and Schipper, H.M. (1995) Differential effects of cysteamine on heat shock protein induction and cytoplasmic granulation in astrocytes and glioma cells.Mol. Brain Res. 31, 173–184.

    Article  PubMed  CAS  Google Scholar 

  • Connor, J.R., Menzies, S.L., St. Martin, S.M. and Mufson, E.J. (1992) A histochemical study of iron, transferrin, and ferritin in Alzheimer’s diseased brains.J. Neurosci. Res. 31, 75–83.

    Article  PubMed  CAS  Google Scholar 

  • Di Monte, D. (1998) Parkinson’s disease. In: Schipper, H.M. (Ed.),Astrocytes in Brain Aging and Neurodegeneration (Austin, TX: R.G. Landes Co.), pp. 111–126.

    Google Scholar 

  • Di Monte, D.A., Schipper, H.M., Hetts, S. and Langston, J.W. (1995) Iron-mediated bioactivation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in glial cultures.Glia 15, 203–206.

    Article  PubMed  Google Scholar 

  • Dore, S., Takahashi, M., Ferris, C.D., Hester, L.D., Guastella, D. and Snyder, S.H. (1999) Bilirubin, formed by activation of heme oxygenase-2, protects neurons against oxidative stress injury.Proc. Natl. Acad. Sci. USA 96, 2445–2450.

    Article  PubMed  CAS  Google Scholar 

  • Dwyer, B.E., Nishimura, R.N., de Vellis, J. and Yoshida, T. (1992) Heme oxygenase is a heat shock protein and PEST protein in rat astroglial cells.Glia 5, 300–305.

    Article  PubMed  CAS  Google Scholar 

  • Dyrks, T., Weidemann, A., Multhaup, G.et al. (1988) Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer’s disease.EMBO J. 7, 949–957.

    PubMed  CAS  Google Scholar 

  • Ewing, J.F., Haber, S.N. and Maines, M.D. (1992) Normal and heat-induced patterns of expression of heme oxygenase-1 (HSP32) in rat brain: hyperthermia causes rapid induction of mRNA and protein.J. Neuwchem. 58, 1140–1149.

    Article  CAS  Google Scholar 

  • Ewing, J.F. and Maines, M.D. (1991) Rapid induction of heme oxygenase 1 mRNA and protein by hyperthermia in rat brain: heme oxygenase 2 is not a heat shock protein.Proc. Natl. Acad. Sci. USA 88, 5364–5368.

    Article  PubMed  CAS  Google Scholar 

  • Faucheux, B.A., Hirsch, E.C., Villares, T., Selimi, E, Mouatt-Prigent, A., Javoy-Agid, F, Hauw, J.J. and Agid, Y. (1993) Distribution of125I-ferrotransferrin binding sites in the mesencephalon of control subjects and patients with Parkinson’s disease.J. Neurochem. 60, 2338–2341.

    Article  PubMed  CAS  Google Scholar 

  • Frankel, D. and Schipper, H.M. (1997) Does astroglial senescence facilitate oxidative neuronal injury?Soc. Neurosci. 23, 1371 (abstract).

    Google Scholar 

  • Gelman, B.B. (1995) Iron in CNS disease.J. Neuropathol. Exp. Neurol. 54, 477–486.

    Article  PubMed  CAS  Google Scholar 

  • Janetzky, B., Reichman, H, Youdim, M.B.N,et al. (1997) Iron and oxidative damage in neurodegenerative diseases. In: Beal, M.F., Howell, N. and Bodis-Walker, I. (Eds.),Mitochondria and Free Radicals in Neurodegenerative Diseases (Wiley-Liss), Vol. 20, 407–421.

    Google Scholar 

  • Jellinger, P., Paulus, W., Grundke-Iqbal, I.et al. (1990) Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases.J. Neural Transm. Park. Dis. Dement. Sect. 2, 327–340.

    Article  PubMed  CAS  Google Scholar 

  • Jenner, P. (1992) What process causes nigral cell death in Parkinson’s disease. In: Cederbaum, J.M. and Gancher, S.T. (Eds.),Neurological Clinics, Part 2: Parkinson’s Disease. (Philadelphia: Saunders Co.), pp. 387–403.

    Google Scholar 

  • Kalaria, R.N., Sromek, S.M., Grahovac, I. and Harik, S.I. (1992) Transferrin receptors of rat and human brain and cerebral microvessels and their status in Alzheimer’s disease.Brain Res. 585, 87–93.

    Article  PubMed  CAS  Google Scholar 

  • Keyse, S.M. and Tyrell, R.M. (1987) Both near ultraviolet radiation and the oxidizing agent hydrogen peroxide induce a 32-kDa stress protein in normal human skin fibroblasts.J. Biol. Chem. 262, 14821–14825.

    PubMed  CAS  Google Scholar 

  • Keyse, S.M. and Tyrell, R.M. (1989) Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite.Proc. Natl. Acad. Sci. USA 86, 99–103.

    Article  PubMed  CAS  Google Scholar 

  • Klausner, R.D., Rouault, T.A. and Harford, J.B. (1993) Regulating the fate of mRNA: the control of cellular iron metabolism.Cell 72, 19–28.

    Article  PubMed  CAS  Google Scholar 

  • Kontos, H., Wei, W, Ellis, E., Jenkins, L., Povishock, J., Rowe, G. and Hess, M. (1985) Appearance of superoxide anion radical in cerebral extracellular space during increased prostaglandin synthesis in cats.Circ. Res. 57, 142.

    PubMed  CAS  Google Scholar 

  • Maines, M.D. and Kappas, A. (1974) Cobalt induction of hepatic heme oxygenase; with evidence that cytochrome P-450 is not essential for this enzyme activity.Proc. Natl. Acad. Sci. USA 71, 4293–4297.

    Article  PubMed  CAS  Google Scholar 

  • Manganaro, R, Chopra, VS., Mydlarski, M.B., Bernatchez, G. and Schipper, H.M. (1995) Redox perturbations in cysteamine-stressed astroglia: implications for inclusion formation and gliosis in the aging brain.Free Rad. Biol. Med. 19, 823–835.

    Article  PubMed  CAS  Google Scholar 

  • Mash, D.C., Pablo, J., Buck, B.E., Sanchez-Ramos, J. and Weiner, W.J. (1991) Distribution and number of transferrin receptors in Parkinson’s disease and in MPTP-treated mice.Exp. Neurol. 114, 73–81.

    Article  PubMed  CAS  Google Scholar 

  • Mattson, M.P. (1997) Cellular actions of ß-amyloid precursor protein and its soluble and fibrillogenic derivatives.Physiol. Rev. 77, 1081–1132.

    PubMed  CAS  Google Scholar 

  • Metodiewa, D., Reszka, K. and Dunford, H. (1989) Evidence for a peroxidatic oxidation of norepinephrine, a catecholamine, by lactoperoxidase.Biochem. Biophys. Res. Commun. 160, 1183–1188.

    Article  PubMed  CAS  Google Scholar 

  • Morris, C.M. and Edwardson, J.A. (1994) Iron histochemistry of the substantia nigra in Parkinson’s disease.Neurodegen-eration 3, 277–282.

    CAS  Google Scholar 

  • Morris, CM., Kerwin, J.M. and Edwarsan, J.A. (1994) Non-haem iron histochemistry of the normal and Alzheimer’s disease hippocampus.Neurodegeneration 3, 267–275.

    PubMed  CAS  Google Scholar 

  • Mydlarski, M.B., Brawer, J.R. and Schipper, H.M. (1998) The peroxidase-positive subcortical glial system. In: Schipper, H.M. (Ed.),Astrocytes in Brain Aging and Neurodegeneration (Austin, TX: R.G. Landes Co.), pp. 191–206.

    Google Scholar 

  • Mydlarski, M.B., Liberman, A. and Schipper, H.M. (1995) Estrogen induction of glial heat shock proteins: implications for hypothalamic aging.Neurobiol. Aging 16, 977–981.

    Article  PubMed  CAS  Google Scholar 

  • Mydlarski, M.B. and Schipper, H.M. (1998) Astrocyte granu-logenesis and the cellular stress response. In: Schipper, H.M. (Ed.),Astrocytes in Brain Aging and Neurodegeneration, (Austin, TX: R.G. Landes Co.), pp. 207–234.

    Google Scholar 

  • Newcomer, T.A., Rosenberg, P.A. and Aizenman, E. (1995) Iron-mediated oxidation of 3,4-dihydrophenylalanine to an excitotoxin.J. Neurochem. 64, 1742–1748.

    Article  PubMed  CAS  Google Scholar 

  • Pelham, H.R.B. (1985) Activation of heat-shock genes in eukaryotes.Trends Genet. 1, 31–35.

    Article  CAS  Google Scholar 

  • Peterson, T., Peterson, M. and Williams, C. (1989) The role of heme oxygenase and aryl hydrocarbon hydroxylase in the protection by cysteamine from acetaminophen hepatotoxi-city.Toxicol. Appl. Pharmacol. 97, 430–439.

    Article  PubMed  CAS  Google Scholar 

  • Ponka, P. (1994) Physiology and pathophysiology of iron metabolism: implications for iron chelation therapy in iron overload. In: Bergeron, R.J. and Brittehham, G.M. (Eds.),The Development of Iron Chelators for Clinical Use (CRC Press) pp. 1–32.

  • Riederer, P., Sofic, E., Rausch, W.D., Schmidt B., Reynolds, G.P., Jellinger, K. and Youdim, M.B. (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains.J. Neurochem. 52, 515–520.

    Article  PubMed  CAS  Google Scholar 

  • Schipper, H.M. (1996) Astrocytes, brain aging and neurode-generation.Neurobiol. Aging 17, 467–480.

    Article  PubMed  CAS  Google Scholar 

  • Schipper, H.M. (1998) Glial iron sequestration and neurode-generation. In: Schipper, H.M. (Ed.),Astrocytes in Brain Aging and Neurodegeneration (Austin, TX: R.G. Landes Co.), pp. 235–251.

    Google Scholar 

  • Schipper, H.M., Bernier, L., Mehindate, K. and Frankel, D. (1999) Mitochondrial iron sequestration in dopamine-challenged astroglia: Role of heme oxygenase-1 and the permeability transition pore.J. Neurochem. 72, 1802–1811.

    Article  PubMed  CAS  Google Scholar 

  • Schipper, H.M., Cisse, S. and Stopa, E.G. (1995) Expression of heme oxygenase-1 in senescent and Alzheimer-diseased brain.Ann. Neurol. 37, 758–768.

    Article  PubMed  CAS  Google Scholar 

  • Schipper, H.M., Kotake, Y. and Janzen, E.G. (1991) Catechol oxidation by peroxidase-positive astrocytes in primary culture: an electron spin resonance study.J. Neurosci. 11, 2170–2176.

    PubMed  CAS  Google Scholar 

  • Schipper, H.M., Liberman, A. and Stopa, E.G. (1998) Neural heme oxygenase-1 expression in idiopathic Parkinson’s disease.Exp. Neurol. 150, 60–68.

    Article  PubMed  CAS  Google Scholar 

  • Tenhunen, R., Marver, H.S. and Schmid, R. (1969) Microsomal heme oxygenase: characterization of the enzyme.J. Biol. Chem. 244, 6388–6394.

    PubMed  CAS  Google Scholar 

  • Thiel, E.C. (1990) Regulation of ferritin and transferrin receptor mRNAs.J. Biol. Chem. 265, 4771–4774.

    Google Scholar 

  • Wang, X., Manganaro, E and Schipper, H.M. (1995) A cellular stress model for the sequestration of redox-active glial iron in the aging and degenerating nervous system.J. Neurochem. 64, 1868–1877.

    PubMed  CAS  Google Scholar 

  • Youdim, M.B.H. (1994) Inorganic neurotoxins in neurodegenerative disorders without primary dementia. In: Calne, D.B. (Ed.)Neurodegenerative Diseases (Philadelphia: Saunders WB Co.), 251–276.

    Google Scholar 

  • Youdim, M.B.H., Ben-Shachar, D. and Riederer, P. (1993) The role of iron in etiopathology of Parkinson’s disease.Mov. Disord. 8, 1–12.

    Article  PubMed  CAS  Google Scholar 

  • Zernlan, F.P., Thienhaus, O.J. and Bosmann, H.B. (1989) Superoxide dismutase activity in Alzheimer’s disease: possible mechanism for paired helical filament formation.Brain Res. 476, 160–162.

    Article  Google Scholar 

  • Zhang, J. and Piantadosi, C.A. (1992) Mitochondrial oxidative stress after carbon monoxide hypoxia in the rat brain.J. Clin. Invest. 90, 1193–1199.

    Article  PubMed  CAS  Google Scholar 

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  1. Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, 3755 Cote Ste. Catherine Road, H3T 1E2, Montreal, Quebec, Canada

    Hyman M. Schipper

  2. Department of Neurology and Neurosurgery, and Department of Medicine, (Geriatrics) McGill University, Montreal, Canada

    Hyman M. Schipper

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Schipper, H.M. Glial HO-1 expression, iron deposition and oxidative stress in neurodegenerative diseases. neurotox res 1, 57–70 (1999). https://doi.org/10.1007/BF03033339

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