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Nitric Oxide-Mediated Oxidative Damage and the Progressive Demise of Motor Neurons in ALS

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Abstract

Oxidative damage is a common and early feature of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders. Dr. Mark Smith and his colleagues have built the case for oxidative stress being a primary progenitor rather than a secondary end-stage epiphenomenon of neurodegeneration. They proposed that reactive oxygen species contribute to the “age-related cascade of neurodegeneration,” whereby accumulative oxidative damage with age promotes other characteristic pathological changes in afflicted brain regions, including protein aggregation, metabolic deficiencies, and inflammation. Nitric oxide (NO) likely plays a critical role in this age-related cascade. NO is a major signaling molecule produced in the central nervous system to modulate neurological activity through stimulating cyclic GMP synthesis. However, the same physiological concentrations of NO, relevant in cellular signaling, may also initiate and amplify oxidative damage by diffusion-limited reactions with superoxide (O •−2 ) to produce peroxynitrite (ONOO). This is perhaps best illustrated in ALS where physiological levels of NO promote survival of motor neurons, but the same concentrations can stimulate motor neuron apoptosis and glial cell activation under pathological conditions. While these changes represent a complex mechanism involving multiple cell types in the pathogenesis of ALS, they also reveal general processes underlying neurodegeneration.

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References

  • Alexianu ME, Kozovska M, Appel SH (2001) Immune reactivity in a mouse model of familial ALS correlates with disease progression. Neurology 57:1282–1289

    Article  PubMed  CAS  Google Scholar 

  • Almer G, Vukosavic S, Romero N, Przedborski S (1999) Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 72:2415–2425

    Article  PubMed  CAS  Google Scholar 

  • Andreassen OA, Ferrante RJ, Klivenyi P, Klein AM, Shinobu LA, Epstein CJ, Beal MF (2000) Partial deficiency of manganese superoxide dismutase exacerbates a transgenic mouse model of amyotrophic lateral sclerosis. Ann Neurol 47:447–455

    Article  PubMed  CAS  Google Scholar 

  • Aoyama K, Matsubara K, Fujikawa Y, Nagahiro Y, Shimizu K, Umegae N, Hayase N, Shiono H, Kobayashi S (2000) Nitration of manganese superoxide dismutase in cerebrospinal fluids is a marker for peroxynitrite-mediated oxidative stress in neurodegenerative diseases. Ann Neurol 47:524–527

    Article  PubMed  CAS  Google Scholar 

  • Barbeito LH, Pehar M, Cassina P, Vargas MR, Peluffo H, Viera L, Estevez AG, Beckman JS (2004) A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Res Brain Res Rev 47:263–274

    Article  PubMed  CAS  Google Scholar 

  • Barker PA (2004) p75NTR is positively promiscuous: novel partners and new insights. Neuron 42:529–533

    Article  PubMed  CAS  Google Scholar 

  • Bayir H, Kagan VE, Clark RS, Janesko-Feldman K, Rafikov R, Huang Z, Zhang X, Vagni V, Billiar TR, Kochanek PM (2007) Neuronal NOS-mediated nitration and inactivation of manganese superoxide dismutase in brain after experimental and human brain injury. J Neurochem 101:168–181

    Article  PubMed  CAS  Google Scholar 

  • Beal MF, Ferrante RJ, Browne SE, Matthews RT, Kowall NW, Brown RH Jr (1997) Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis. Ann Neurol 42:644–654

    Article  PubMed  CAS  Google Scholar 

  • Beckman JS (1996) Oxidative damage and tyrosine nitration from peroxynitrite. Chem Res Toxicol 9:836–844

    Article  PubMed  CAS  Google Scholar 

  • Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271:C1424–C1437

    PubMed  CAS  Google Scholar 

  • Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624

    Article  PubMed  CAS  Google Scholar 

  • Beckman JS, Carson M, Smith CD, Koppenol WH (1993) ALS, SOD and peroxynitrite. Nature 364:584

    Article  PubMed  CAS  Google Scholar 

  • Beckman JS, Ye YZ, Anderson PG, Chen J, Accavitti MA, Tarpey MM, White CR (1994) Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. Biol Chem Hoppe Seyler 375:81–88

    Article  Google Scholar 

  • Bendotti C, Atzori C, Piva R, Tortarolo M, Strong MJ, DeBiasi S, Migheli A (2004) Activated p38MAPK is a novel component of the intracellular inclusions found in human amyotrophic lateral sclerosis and mutant SOD1 transgenic mice. J Neuropathol Exp Neurol 63:113–119

    PubMed  CAS  Google Scholar 

  • Blaauwgeers HG, Vianney de Jong JM, Verspaget HW, van den Berg FM, Troost D (1996) Enhanced superoxide dismutase-2 immunoreactivity of astrocytes and occasional neurons in amyotrophic lateral sclerosis. J Neurol Sci 140:21–29

    Article  PubMed  CAS  Google Scholar 

  • Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392

    Article  PubMed  CAS  Google Scholar 

  • Bolanos JP, Medina JM (1996) Induction of nitric oxide synthase inhibits gap junction permeability in cultured rat astrocytes. J Neurochem 66:2091–2099

    Article  PubMed  CAS  Google Scholar 

  • Bolanos JP, Heales SJ, Land JM, Clark JB (1995) Effect of peroxynitrite on the mitochondrial respiratory chain: differential susceptibility of neurones and astrocytes in primary culture. J Neurochem 64:1965–1972

    Article  PubMed  CAS  Google Scholar 

  • Bonda DJ, Wang X, Perry G, Nunomura A, Tabaton M, Zhu X, Smith MA (2010) Oxidative stress in Alzheimer disease: a possibility for prevention. Neuropharmacology 59:290–294

    Article  PubMed  CAS  Google Scholar 

  • Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA (1995) Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 92:7162–7166

    Article  PubMed  CAS  Google Scholar 

  • Bruijn LI, Becher MW, Lee MK, Anderson KL, Jenkins NA, Copeland NG, Sisodia SS, Rothstein JD, Borchelt DR, Price DL, Cleveland DW (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338

    Article  PubMed  CAS  Google Scholar 

  • Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, Reaume AG, Scott RW, Cleveland DW (1998) Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281:1851–1854

    Article  PubMed  CAS  Google Scholar 

  • Calabrese V, Cornelius C, Rizzarelli E, Owen JB, Dinkova-Kostova AT, Butterfield DA (2009) Nitric oxide in cell survival: a Janus molecule. Antioxid Redox Signal 11:2717–2739

    Article  PubMed  CAS  Google Scholar 

  • Calcerrada P, Peluffo G, Radi R (2011) Nitric oxide-derived oxidants with a focus on peroxynitrite: molecular targets, cellular responses and therapeutic implications. Curr Pharm Des 17(35):3905–3932

    Article  PubMed  CAS  Google Scholar 

  • Casoni F, Basso M, Massignan T, Gianazza E, Cheroni C, Salmona M, Bendotti C, Bonetto V (2005) Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: possible multifunctional role in the pathogenesis. J Biol Chem 280:16295–16304

    Article  PubMed  CAS  Google Scholar 

  • Cassina AM, Hodara R, Souza JM, Thomson L, Castro L, Ischiropoulos H, Freeman BA, Radi R (2000) Cytochrome c nitration by peroxynitrite. J Biol Chem 275:21409–21415

    Article  PubMed  CAS  Google Scholar 

  • Cassina P, Peluffo H, Pehar M, Martinez-Palma L, Ressia A, Beckman JS, Estevez AG, Barbeito L (2002) Peroxynitrite triggers a phenotypic transformation in spinal cord astrocytes that induces motor neuron apoptosis. J Neurosci Res 67:21–29

    Article  PubMed  CAS  Google Scholar 

  • Cassina P, Pehar M, Vargas MR, Castellanos R, Barbeito AG, Estevez AG, Thompson JA, Beckman JS, Barbeito L (2005) Astrocyte activation by fibroblast growth factor-1 and motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J Neurochem 93:38–46

    Article  PubMed  CAS  Google Scholar 

  • Cassina P, Cassina A, Pehar M, Castellanos R, Gandelman M, de Leon A, Robinson KM, Mason RP, Beckman JS, Barbeito L, Radi R (2008) Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci 28:4115–4122

    Article  PubMed  CAS  Google Scholar 

  • Chao MV (2003) Neurotrophins and their receptors: a convergence point for many signalling pathways. Nat Rev Neurosci 4:299–309

    Article  PubMed  CAS  Google Scholar 

  • Chen K, Northington FJ, Martin LJ (2010) Inducible nitric oxide synthase is present in motor neuron mitochondria and Schwann cells and contributes to disease mechanisms in ALS mice. Brain Struct Funct 214:219–234

    Article  PubMed  CAS  Google Scholar 

  • Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM (1995) FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 81:505–512

    Article  PubMed  CAS  Google Scholar 

  • Chinta SJ, Andersen JK (2011) Nitrosylation and nitration of mitochondrial complex I in Parkinson’s disease. Free Radic Res 45:53–58

    Article  PubMed  CAS  Google Scholar 

  • Chou SM, Wang HS, Komai K (1996a) Colocalization of NOS and SOD1 in neurofilament accumulation within motor neurons of amyotrophic lateral sclerosis: an immunohistochemical study. J Chem Neuroanat 10:249–258

    Article  PubMed  CAS  Google Scholar 

  • Chou SM, Wang HS, Taniguchi A (1996b) Role of SOD-1 and nitric oxide/cyclic GMP cascade on neurofilament aggregation in ALS/MND. J Neurol Sci 139(Suppl):16–26

    Article  PubMed  Google Scholar 

  • Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH Jr, Julien JP, Goldstein LS, Cleveland DW (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113–117

    Article  PubMed  CAS  Google Scholar 

  • Crow JP, Sampson JB, Zhuang Y, Thompson JA, Beckman JS (1997a) Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J Neurochem 69:1936–1944

    Article  PubMed  CAS  Google Scholar 

  • Crow JP, Ye YZ, Strong M, Kirk M, Barnes S, Beckman JS (1997b) Superoxide dismutase catalyzes nitration of tyrosines by peroxynitrite in the rod and head domains of neurofilament-l. J Neurochem 69:1945–1953

    Article  PubMed  CAS  Google Scholar 

  • Crutcher KA, Scott SA, Liang S, Everson WV, Weingartner J (1993) Detection of NGF-like activity in human brain tissue: increased levels in Alzheimer’s disease. J Neurosci 13:2540–2550

    PubMed  CAS  Google Scholar 

  • Cuevas P, Carceller F, Gimenez-Gallego G (1995) Acidic fibroblast growth factor prevents death of spinal cord motoneurons in newborn rats after nerve section. Neurol Res 17:396–399

    PubMed  CAS  Google Scholar 

  • Dawson VL, Brahmbhatt HP, Mong JA, Dawson TM (1994) Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures. Neuropharmacology 33:1425–1430

    Article  PubMed  CAS  Google Scholar 

  • Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10:608–614

    Article  PubMed  CAS  Google Scholar 

  • Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC (2008) Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3:637–648

    Article  PubMed  CAS  Google Scholar 

  • Elde R, Cao YH, Cintra A, Brelje TC, Pelto-Huikko M, Junttila T, Fuxe K, Pettersson RF, Hokfelt T (1991) Prominent expression of acidic fibroblast growth factor in motor and sensory neurons. Neuron 7:349–364

    Article  PubMed  CAS  Google Scholar 

  • Estevez AG, Radi R, Barbeito L, Shin JT, Thompson JA, Beckman JS (1995) Peroxynitrite-induced cytotoxicity in PC12 cells: evidence for an apoptotic mechanism differentially modulated by neurotrophic factors. J Neurochem 65:1543–1550

    Article  PubMed  CAS  Google Scholar 

  • Estevez AG, Spear N, Manuel SM, Radi R, Henderson CE, Barbeito L, Beckman JS (1998a) Nitric oxide and superoxide contribute to motor neuron apoptosis induced by trophic factor deprivation. J Neurosci 18:923–931

    PubMed  CAS  Google Scholar 

  • Estevez AG, Spear N, Thompson JA, Cornwell TL, Radi R, Barbeito L, Beckman JS (1998b) Nitric oxide-dependent production of cGMP supports the survival of rat embryonic motor neurons cultured with brain-derived neurotrophic factor. J Neurosci 18:3708–3714

    PubMed  CAS  Google Scholar 

  • Estevez AG, Crow JP, Sampson JB, Reiter C, Zhuang Y, Richardson GJ, Tarpey MM, Barbeito L, Beckman JS (1999) Induction of nitric oxide-dependent apoptosis in motor neurons by zinc-deficient superoxide dismutase. Science 286:2498–2500

    Article  PubMed  CAS  Google Scholar 

  • Estevez AG, Kamaid A, Thompson JA, Cornwell TL, Radi R, Barbeito L, Beckman JS (2002) Cyclic guanosine 5′ monophosphate (GMP) prevents expression of neuronal nitric oxide synthase and apoptosis in motor neurons deprived of trophic factors in rats. Neurosci Lett 326:201–205

    Article  PubMed  CAS  Google Scholar 

  • Fahnestock M, Scott SA, Jette N, Weingartner JA, Crutcher KA (1996) Nerve growth factor mRNA and protein levels measured in the same tissue from normal and Alzheimer’s disease parietal cortex. Brain Res Mol Brain Res 42:175–178

    Article  PubMed  CAS  Google Scholar 

  • Ferrante RJ, Shinobu LA, Schulz JB, Matthews RT, Thomas CE, Kowall NW, Gurney ME, Beal MF (1997) Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation. Ann Neurol 42:326–334

    Article  PubMed  CAS  Google Scholar 

  • Figlewicz DA, Krizus A, Martinoli MG, Meininger V, Dib M, Rouleau GA, Julien JP (1994) Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum Mol Genet 3:1757–1761

    Article  PubMed  CAS  Google Scholar 

  • Gong YH, Parsadanian AS, Andreeva A, Snider WD, Elliott JL (2000) Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. J Neurosci 20:660–665

    PubMed  CAS  Google Scholar 

  • Greenacre SA, Ischiropoulos H (2001) Tyrosine nitration: localisation, quantification, consequences for protein function and signal transduction. Free Radic Res 34:541–581

    Article  PubMed  CAS  Google Scholar 

  • Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, Caliendo J, Hentati A, Kwon YW, Deng HX et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775

    Article  PubMed  CAS  Google Scholar 

  • Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD, Rao M, Eagle A, Kammesheidt A, Christensen A, Mendell JR, Burghes AH, Kaspar BK (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824–828

    Article  PubMed  CAS  Google Scholar 

  • Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23:249–256

    Article  PubMed  CAS  Google Scholar 

  • Henkel JS, Engelhardt JI, Siklos L, Simpson EP, Kim SH, Pan T, Goodman JC, Siddique T, Beers DR, Appel SH (2004) Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol 55:221–235

    Article  PubMed  CAS  Google Scholar 

  • Hensley K, Abdel-Moaty H, Hunter J, Mhatre M, Mou S, Nguyen K, Potapova T, Pye QN, Qi M, Rice H, Stewart C, Stroukoff K, West M (2006) Primary glia expressing the G93A-SOD1 mutation present a neuroinflammatory phenotype and provide a cellular system for studies of glial inflammation. J Neuroinflammation 3:2

    Article  PubMed  CAS  Google Scholar 

  • Hewett SJ, Csernansky CA, Choi DW (1994) Selective potentiation of NMDA-induced neuronal injury following induction of astrocytic iNOS. Neuron 13:487–494

    Article  PubMed  CAS  Google Scholar 

  • Hirano A (1991) Cytopathology of amyotrophic lateral sclerosis. Adv Neurol 56:91–101

    PubMed  CAS  Google Scholar 

  • Hoffman PN, Cleveland DW, Griffin JW, Landes PW, Cowan NJ, Price DL (1987) Neurofilament gene expression: a major determinant of axonal caliber. Proc Natl Acad Sci USA 84:3472–3476

    Article  PubMed  CAS  Google Scholar 

  • Howland DS, Liu J, She Y, Goad B, Maragakis NJ, Kim B, Erickson J, Kulik J, DeVito L, Psaltis G, DeGennaro LJ, Cleveland DW, Rothstein JD (2002) Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA 99:1604–1609

    Article  PubMed  CAS  Google Scholar 

  • Hughes RA, Sendtner M, Thoenen H (1993) Members of several gene families influence survival of rat motoneurons in vitro and in vivo. J Neurosci Res 36:663–671

    Article  PubMed  CAS  Google Scholar 

  • Ischiropoulos H (2003) Biological selectivity and functional aspects of protein tyrosine nitration. Biochem Biophys Res Commun 305:776–783

    Article  PubMed  CAS  Google Scholar 

  • Ischiropoulos H, Zhu L, Chen J, Tsai M, Martin JC, Smith CD, Beckman JS (1992) Peroxynitrite-mediated tyrosine nitration catalyzed by superoxide dismutase. Arch Biochem Biophys 298:431–437

    Article  PubMed  CAS  Google Scholar 

  • Katzman R (1986) Alzheimer’s disease. N Engl J Med 314:964–973

    Article  PubMed  CAS  Google Scholar 

  • Kawamata T, Akiyama H, Yamada T, McGeer PL (1992) Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol 140:691–707

    PubMed  CAS  Google Scholar 

  • Koppenol WH, Moreno JJ, Pryor WA, Ischiropoulos H, Beckman JS (1992) Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem Res Toxicol 5:834–842

    Article  PubMed  CAS  Google Scholar 

  • Kresse A, Pettersson R, Hokfelt T (1995) Distribution of acidic fibroblast growth factor mRNA-expressing neurons in the adult mouse central nervous system. J Comp Neurol 359:323–339

    Article  PubMed  CAS  Google Scholar 

  • Landriscina M, Bagala C, Mandinova A, Soldi R, Micucci I, Bellum S, Prudovsky I, Maciag T (2001) Copper induces the assembly of a multiprotein aggregate implicated in the release of fibroblast growth factor 1 in response to stress. J Biol Chem 276:25549–25557

    Article  PubMed  CAS  Google Scholar 

  • Lebovitz RM, Zhang H, Vogel H, Cartwright J Jr, Dionne L, Lu N, Huang S, Matzuk MM (1996) Neurodegeneration, myocardial injury, and perinatal death in mitochondrial superoxide dismutase-deficient mice. Proc Natl Acad Sci USA 93:9782–9787

    Article  PubMed  CAS  Google Scholar 

  • Lee MK, Marszalek JR, Cleveland DW (1994) A mutant neurofilament subunit causes massive, selective motor neuron death: implications for the pathogenesis of human motor neuron disease. Neuron 13:975–988

    Article  PubMed  CAS  Google Scholar 

  • Levine JB, Kong J, Nadler M, Xu Z (1999) Astrocytes interact intimately with degenerating motor neurons in mouse amyotrophic lateral sclerosis (ALS). Glia 28:215–224

    Article  PubMed  CAS  Google Scholar 

  • Lowry KS, Murray SS, McLean CA, Talman P, Mathers S, Lopes EC, Cheema SS (2001) A potential role for the p75 low-affinity neurotrophin receptor in spinal motor neuron degeneration in murine and human amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2:127–134

    Article  PubMed  CAS  Google Scholar 

  • MacMillan-Crow LA, Crow JP, Kerby JD, Beckman JS, Thompson JA (1996) Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts. Proc Natl Acad Sci USA 93:11853–11858

    Article  PubMed  CAS  Google Scholar 

  • MacMillan-Crow LA, Crow JP, Thompson JA (1998) Peroxynitrite-mediated inactivation of manganese superoxide dismutase involves nitration and oxidation of critical tyrosine residues. Biochemistry 37:1613–1622

    Article  PubMed  CAS  Google Scholar 

  • Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH (2008) Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3:649–657

    Article  PubMed  CAS  Google Scholar 

  • Martin LJ, Kaiser A, Price AC (1999) Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis. J Neurobiol 40:185–201

    Article  PubMed  CAS  Google Scholar 

  • Martin LJ, Chen K, Liu Z (2005) Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked by DNA damage and p53 activation. J Neurosci 25:6449–6459

    Article  PubMed  CAS  Google Scholar 

  • McGeer PL, McGeer EG (2002) Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26:459–470

    Article  PubMed  CAS  Google Scholar 

  • Migheli A, Cordera S, Bendotti C, Atzori C, Piva R, Schiffer D (1999) S-100beta protein is upregulated in astrocytes and motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis. Neurosci Lett 261:25–28

    Article  PubMed  CAS  Google Scholar 

  • Moreno-Lopez B, Sunico CR, Gonzalez-Forero D (2011) NO orchestrates the loss of synaptic boutons from adult “sick” motoneurons: modeling a molecular mechanism. Mol Neurobiol 43:41–66

    Article  PubMed  CAS  Google Scholar 

  • Muzio M, Chinnaiyan AM, Kischkel FC, O’Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85:817–827

    Article  PubMed  CAS  Google Scholar 

  • Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615–622

    Article  PubMed  CAS  Google Scholar 

  • Nunomura A, Perry G, Pappolla MA, Friedland RP, Hirai K, Chiba S, Smith MA (2000) Neuronal oxidative stress precedes amyloid-beta deposition in Down syndrome. J Neuropathol Exp Neurol 59:1011–1017

    PubMed  CAS  Google Scholar 

  • Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA (2001) Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol 60:759–767

    PubMed  CAS  Google Scholar 

  • Nykjaer A, Willnow TE, Petersen CM (2005) p75NTR—live or let die. Curr Opin Neurobiol 15:49–57

    Article  PubMed  CAS  Google Scholar 

  • Olsen MK, Roberds SL, Ellerbrock BR, Fleck TJ, McKinley DK, Gurney ME (2001) Disease mechanisms revealed by transcription profiling in SOD1-G93A transgenic mouse spinal cord. Ann Neurol 50:730–740

    Article  PubMed  CAS  Google Scholar 

  • Oppenheim RW (1996) Neurotrophic survival molecules for motoneurons: an embarrassment of riches. Neuron 17:195–197

    Article  PubMed  CAS  Google Scholar 

  • Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424

    Article  PubMed  CAS  Google Scholar 

  • Palacios-Callender M, Quintero M, Hollis VS, Springett RJ, Moncada S (2004) Endogenous NO regulates superoxide production at low oxygen concentrations by modifying the redox state of cytochrome c oxidase. Proc Natl Acad Sci USA 101:7630–7635

    Article  PubMed  CAS  Google Scholar 

  • Pehar M, Cassina P, Vargas MR, Castellanos R, Viera L, Beckman JS, Estevez AG, Barbeito L (2004) Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis. J Neurochem 89:464–473

    Article  PubMed  CAS  Google Scholar 

  • Pehar M, Cassina P, Vargas MR, Xie Y, Beckman JS, Massa SM, Longo FM, Barbeito L (2006a) Modulation of p75-dependent motor neuron death by a small non-peptidyl mimetic of the neurotrophin loop 1 domain. Eur J Neurosci 24:1575–1580

    Article  PubMed  Google Scholar 

  • Pehar M, Vargas MR, Robinson KM, Cassina P, England P, Beckman JS, Alzari PM, Barbeito L (2006b) Peroxynitrite transforms nerve growth factor into an apoptotic factor for motor neurons. Free Radic Biol Med 41:1632–1644

    Article  PubMed  CAS  Google Scholar 

  • Pehar M, Vargas MR, Robinson KM, Cassina P, Diaz-Amarilla PJ, Hagen TM, Radi R, Barbeito L, Beckman JS (2007) Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J Neurosci 27:7777–7785

    Article  PubMed  CAS  Google Scholar 

  • Pierson KB, Evenson MA (1988) 200 Kd neurofilament protein binds Al, Cu and Zn. Biochem Biophys Res Commun 152:598–604

    Article  PubMed  CAS  Google Scholar 

  • Pramatarova A, Laganiere J, Roussel J, Brisebois K, Rouleau GA (2001) Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J Neurosci 21:3369–3374

    PubMed  CAS  Google Scholar 

  • Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21:4183–4187

    PubMed  CAS  Google Scholar 

  • Qiu L, Rivera-Perez JA, Xu Z (2011) A non-specific effect associated with conditional transgene expression based on Cre-loxP strategy in mice. PLoS ONE 6:e18778

    Article  PubMed  CAS  Google Scholar 

  • Radi R (1998) Peroxynitrite reactions and diffusion in biology. Chem Res Toxicol 11:720–721

    Article  PubMed  CAS  Google Scholar 

  • Radi R, Cassina A, Hodara R, Quijano C, Castro L (2002) Peroxynitrite reactions and formation in mitochondria. Free Radic Biol Med 33:1451–1464

    Article  PubMed  CAS  Google Scholar 

  • Raoul C, Henderson CE, Pettmann B (1999) Programmed cell death of embryonic motoneurons triggered through the FAS death receptor. J Cell Biol 147:1049–1062

    Article  PubMed  CAS  Google Scholar 

  • Raoul C, Pettmann B, Henderson CE (2000) Active killing of neurons during development and following stress: a role for p75(NTR) and Fas? Curr Opin Neurobiol 10:111–117

    Article  PubMed  CAS  Google Scholar 

  • Raoul C, Estevez AG, Nishimune H, Cleveland DW, deLapeyriere O, Henderson CE, Haase G, Pettmann B (2002) Motoneuron death triggered by a specific pathway downstream of Fas. potentiation by ALS-linked SOD1 mutations. Neuron 35:1067–1083

    Article  PubMed  CAS  Google Scholar 

  • Raoul C, Buhler E, Sadeghi C, Jacquier A, Aebischer P, Pettmann B, Henderson CE, Haase G (2006) Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL. Proc Natl Acad Sci USA 103:6007–6012

    Article  PubMed  CAS  Google Scholar 

  • Reaume AG, Elliott JL, Hoffman EK, Kowall NW, Ferrante RJ, Siwek DF, Wilcox HM, Flood DG, Beal MF, Brown RH Jr, Scott RW, Snider WD (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13:43–47

    Article  PubMed  CAS  Google Scholar 

  • Reynolds MR, Berry RW, Binder LI (2007) Nitration in neurodegeneration: deciphering the “Hows” “nYs”. Biochemistry 46:7325–7336

    Article  PubMed  CAS  Google Scholar 

  • Rhoads TW, Lopez NI, Zollinger DR, Morre JT, Arbogast BL, Maier CS, DeNoyer L, Beckman JS (2011) Measuring copper and zinc superoxide dismutase from spinal cord tissue using electrospray mass spectrometry. Anal Biochem 415:52–58

    Article  PubMed  CAS  Google Scholar 

  • Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

    Article  PubMed  CAS  Google Scholar 

  • Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326:1464–1468

    Article  PubMed  CAS  Google Scholar 

  • Rowland LP, Shneider NA (2001) Amyotrophic lateral sclerosis. N Engl J Med 344:1688–1700

    Article  PubMed  CAS  Google Scholar 

  • Sahawneh MA, Ricart KC, Roberts BR, Bomben VC, Basso M, Ye Y, Sahawneh J, Franco MC, Beckman JS, Estevez AG (2010) Cu,Zn-superoxide dismutase increases toxicity of mutant and zinc-deficient superoxide dismutase by enhancing protein stability. J Biol Chem 285:33885–33897

    Article  PubMed  CAS  Google Scholar 

  • Salvemini D, Little JW, Doyle T, Neumann WL (2011) Roles of reactive oxygen and nitrogen species in pain. Free Radic Biol Med 51:951–966

    Article  PubMed  CAS  Google Scholar 

  • Sasaki S, Shibata N, Komori T, Iwata M (2000) iNOS and nitrotyrosine immunoreactivity in amyotrophic lateral sclerosis. Neurosci Lett 291:44–48

    Article  PubMed  CAS  Google Scholar 

  • Sasaki S, Shibata N, Iwata M (2001a) Neuronal nitric oxide synthase immunoreactivity in the spinal cord in amyotrophic lateral sclerosis. Acta Neuropathol 101:351–357

    PubMed  CAS  Google Scholar 

  • Sasaki S, Warita H, Abe K, Komori T, Iwata M (2001b) EAAT1 and EAAT2 immunoreactivity in transgenic mice with a G93A mutant SOD1 gene. NeuroReport 12:1359–1362

    Article  PubMed  CAS  Google Scholar 

  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin KM, Krammer PH, Peter ME (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J 17:1675–1687

    Article  PubMed  CAS  Google Scholar 

  • Schiffer D, Cordera S, Cavalla P, Migheli A (1996) Reactive astrogliosis of the spinal cord in amyotrophic lateral sclerosis. J Neurol Sci 139(Suppl):27–33

    Article  PubMed  Google Scholar 

  • Seeburger JL, Tarras S, Natter H, Springer JE (1993) Spinal cord motoneurons express p75NGFR and p145trkB mRNA in amyotrophic lateral sclerosis. Brain Res 621:111–115

    Article  PubMed  CAS  Google Scholar 

  • Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657

    PubMed  CAS  Google Scholar 

  • Souza JM, Daikhin E, Yudkoff M, Raman CS, Ischiropoulos H (1999) Factors determining the selectivity of protein tyrosine nitration. Arch Biochem Biophys 371:169–178

    Article  PubMed  CAS  Google Scholar 

  • Stewart VC, Sharpe MA, Clark JB, Heales SJ (2000) Astrocyte-derived nitric oxide causes both reversible and irreversible damage to the neuronal mitochondrial respiratory chain. J Neurochem 75:694–700

    Article  PubMed  CAS  Google Scholar 

  • Stuerenburg HJ, Kunze K (1998) Tissue concentrations of nerve growth factor in aging rat heart and skeletal muscle. Muscle Nerve 21:404–406

    Article  PubMed  CAS  Google Scholar 

  • Surmeli NB, Litterman NK, Miller AF, Groves JT (2010) Peroxynitrite mediates active site tyrosine nitration in manganese superoxide dismutase. Evidence of a role for the carbonate radical anion. J Am Chem Soc (Epub ahead of print)

  • Teng YD, Mocchetti I, Wrathall JR (1998) Basic and acidic fibroblast growth factors protect spinal motor neurones in vivo after experimental spinal cord injury. Eur J Neurosci 10:798–802

    Article  PubMed  CAS  Google Scholar 

  • Teng YD, Mocchetti I, Taveira-DaSilva AM, Gillis RA, Wrathall JR (1999) Basic fibroblast growth factor increases long-term survival of spinal motor neurons and improves respiratory function after experimental spinal cord injury. J Neurosci 19:7037–7047

    PubMed  CAS  Google Scholar 

  • Trotti D, Rossi D, Gjesdal O, Levy LM, Racagni G, Danbolt NC, Volterra A (1996) Peroxynitrite inhibits glutamate transporter subtypes. J Biol Chem 271:5976–5979

    Article  PubMed  CAS  Google Scholar 

  • Trumbull KA, Beckman JS (2009) A role for copper in the toxicity of zinc-deficient superoxide dismutase to motor neurons in amyotrophic lateral sclerosis. Antioxid Redox Signal 11:1627–1639

    Article  PubMed  CAS  Google Scholar 

  • Ugolini G, Raoul C, Ferri A, Haenggeli C, Yamamoto Y, Salaun D, Henderson CE, Kato AC, Pettmann B, Hueber AO (2003) Fas/tumor necrosis factor receptor death signaling is required for axotomy-induced death of motoneurons in vivo. J Neurosci 23:8526–8531

    PubMed  CAS  Google Scholar 

  • Vargas MR, Pehar M, Cassina P, Estevez AG, Beckman JS, Barbeito L (2004) Stimulation of nerve growth factor expression in astrocytes by peroxynitrite. In Vivo 18:269–274

    PubMed  CAS  Google Scholar 

  • Vargas MR, Pehar M, Cassina P, Beckman JS, Barbeito L (2006) Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. J Neurochem 97:687–696

    Article  PubMed  CAS  Google Scholar 

  • Walicke PA (1988) Basic and acidic fibroblast growth factors have trophic effects on neurons from multiple CNS regions. J Neurosci 8:2618–2627

    PubMed  CAS  Google Scholar 

  • Wu W (1993) Expression of nitric-oxide synthase (NOS) in injured CNS neurons as shown by NADPH diaphorase histochemistry. Exp Neurol 120:153–159

    Article  PubMed  CAS  Google Scholar 

  • Wu W, Li L (1993) Inhibition of nitric oxide synthase reduces motoneuron death due to spinal root avulsion. Neurosci Lett 153:121–124

    Article  PubMed  CAS  Google Scholar 

  • Wu W, Li Y, Schinco FP (1994a) Expression of c-jun and neuronal nitric oxide synthase in rat spinal motoneurons following axonal injury. Neurosci Lett 179:157–161

    Article  PubMed  CAS  Google Scholar 

  • Wu W, Liuzzi FJ, Schinco FP, Depto AS, Li Y, Mong JA, Dawson TM, Snyder SH (1994b) Neuronal nitric oxide synthase is induced in spinal neurons by traumatic injury. Neuroscience 61:719–726

    Article  PubMed  CAS  Google Scholar 

  • Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11:251–253

    Article  PubMed  CAS  Google Scholar 

  • Ye Y, Quijano C, Robinson KM, Ricart KC, Strayer AL, Sahawneh MA, Shacka JJ, Kirk M, Barnes S, Accavitti-Loper MA, Radi R, Beckman JS, Estevez AG (2007) Prevention of peroxynitrite-induced apoptosis of motor neurons and PC12 cells by tyrosine-containing peptides. J Biol Chem 282:6324–6337

    Article  PubMed  CAS  Google Scholar 

  • Zhao W, Xie W, Le W, Beers DR, He Y, Henkel JS, Simpson EP, Yen AA, Xiao Q, Appel SH (2004) Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism. J Neuropathol Exp Neurol 63:964–977

    PubMed  CAS  Google Scholar 

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Acknowledgments

This study was financially supported in part by funding from the National Institute of Health grants NIEHS T32ES07060 & P30ES000210, NINDS R01NS058628A, and NCCAM P01AT002034, as well as support from the Amyotrophic Lateral Sclerosis Association (JSB).

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Correspondence to Joseph S. Beckman.

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Drechsel, D.A., Estévez, A.G., Barbeito, L. et al. Nitric Oxide-Mediated Oxidative Damage and the Progressive Demise of Motor Neurons in ALS. Neurotox Res 22, 251–264 (2012). https://doi.org/10.1007/s12640-012-9322-y

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  • DOI: https://doi.org/10.1007/s12640-012-9322-y

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