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NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease

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Abstract

Neurological symptoms and cerebral abnormalities are commonly observed in patients with 3-hydroxy-3-methylglutaryl-CoA lyase (HMG lyase) deficiency, which is biochemically characterized by predominant tissue accumulation of 3-hydroxy-3-methylglutaric (HMG), 3-methylglutaric (MGA), and 3-methylglutaconic (MGT) acids. Since the pathogenesis of this disease is poorly known, the present study evaluated the effects of these compounds on the cytoskeleton phosphorylating system in rat brain. HMG, MGA, and MGT caused hypophosphorylation of glial fibrillary acidic protein (GFAP) and of the neurofilament subunits NFL, NFM, and NFH. HMG-induced hypophosphorylation was mediated by inhibiting the cAMP-dependent protein kinase (PKA) on Ser55 residue of NFL and c-Jun kinase (JNK) by acting on KSP repeats of NFM and NFH subunits. We also evidenced that the subunit NR2B of NMDA receptor and Ca2+ was involved in HMG-elicited hypophosphorylation of cytoskeletal proteins. Furthermore, the antioxidants L-NAME and TROLOX fully prevented both the hypophosphorylation and the inhibition of PKA and JNK caused by HMG, suggesting that oxidative damage may underlie these effects. These findings indicate that the main metabolites accumulating in HMG lyase deficiency provoke hypophosphorylation of cytoskeleton neural proteins with the involvement of NMDA receptors, Ca2+, and reactive species. It is presumed that these alterations may contribute to the neuropathology of this disease.

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References

  • Akashi K, Kakizaki T, Kamiya H, Fukaya M, Yamasaki M, Abe M, Natsume R, Watanabe M, Sakimura K (2009) NMDA receptor GluN2B (GluR epsilon 2/NR2B) subunit is crucial for channel function, postsynaptic macromolecular organization, and actin cytoskeleton at hippocampal CA3 synapses. J Neurosci 29:10869–10882

    Article  PubMed  CAS  Google Scholar 

  • Akerman KE, Wikström MK (1976) Safranine as a probe of the mitochondrial membrane potential. FEBS Lett 68:191–197

    Article  PubMed  CAS  Google Scholar 

  • Baba Y, Hirukawa N, Tanohira N, Sodeoka M (2003) Structure-based design of a highly selective catalytic site-directed inhibitor of ser/Thr protein phosphatase 2B (calcineurin). J Am Chem Soc 125:740–749

    Article  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Brownlees J, Yates A, Bajaj NP, Davis D, Anderton BH, Leigh PN, Shaw CE, Miller CC (2000) Phosphorylation of neurofilament heavy chain side-arms by stress activated protein kinase-1b/Jun N-terminal kinase-3. J Cell Sci 113:401–407

    PubMed  CAS  Google Scholar 

  • Cattani D, Goulart PB, Cavalli VL, Winkelmann-Duarte E, Dos Santos AQ, Pierozan P, de Souza DF, Woehl VM, Fernandes MC, Silva FR, Gonçalves CA, Pessoa-Pureur R, Zamoner A (2013) Congenital hypothyroidism alters the oxidative status, enzyme activities and morphological parameters in the hippocampus of developing rats. Mol Cell Endocrinol 375:14–26

    Article  PubMed  CAS  Google Scholar 

  • Corcoran KA, Leaderbrand K, Radulovic J (2013) Extinction of remotely acquired fear depends on an inhibitory NR2B/PKA pathway in the retrosplenial cortex. J Neurosci 33:19492–19498

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Courtney MJ, Li LL, Lai YY (2014) Mechanisms of NOS1AP action on NMDA receptor-nNOS signaling. Front. Cell Neurosci 8:252

    Article  PubMed  PubMed Central  Google Scholar 

  • da Rosa MS, Seminotti B, Amaral AU, Fernandes CG, Gasparotto J, Moreira JC, Gelain DP, Wajner M, Leipnitz G (2013) Redox homeostasis is compromised in vivo by the metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency in rat cerebral cortex and liver. Free Radic Res 47:1066–1075

    Article  PubMed  Google Scholar 

  • da Silva CG, Ribeiro CA, Leipnitz G, Dutra-Filho CS, Wyse AT, Wannmacher CM, Sarkis JJ, Jakobs C, Wajner M (2002) Inhibition of cytochrome c oxidase activity in rat cerebral cortex and human skeletal muscle by D-2-hydroxyglutaric acid in vitro. Biochim Biophys Acta 1586:81–91

    Article  PubMed  Google Scholar 

  • de Almeida LM, Funchal C, PdeL Pelaez, Pessutto FD, Loureiro SO, Vivian L, Wajner M, Pessoa-Pureur R (2003) Effect of propionic and methylmalonic acids on the in vitro phosphorylation of intermediate filaments from cerebral cortex of rats during development. Metab Brain Dis 18:207–219

    Article  PubMed  Google Scholar 

  • de Mattos-Dutra A, Sampaio de Freitas M, Schröder N, Fogaça Lisboa CS, Pessoa-Pureur R, Wajner M (1997) In vitro phosphorylation of cytoskeletal proteins in the rat cerebral cortex is decreased by propionic acid. Exp Neurol 147:238–247

    Article  PubMed  Google Scholar 

  • Faull K, Bolton P, Halpern B, Hammond J, Danks DM, Hähnel R, Wilkinson SP, Wysocki SJ, Masters PL (1976) Letter: patient with defect in leucine metabolism. N Engl J Med 294:1013

    PubMed  CAS  Google Scholar 

  • Fernandes CG, da Rosa MS, Seminotti B, Pierozan P, Martell RW, Lagranha VL, Busanello EN, Leipnitz G, Wajner M (2013) In vivo experimental evidence that the major metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency induce oxidative stress in striatum of developing rats: a potential pathophysiological mechanism of striatal damage in this disorder. Mol Genet Metab 109:144–153

    Article  PubMed  CAS  Google Scholar 

  • Fischer JC, Ruitenbeek W, Berden JA, Trijbels JM, Veerkamp JH, Stadhouders AM, Sengers RC, Janssen AJ (1985) Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta 153:23–36

    Article  PubMed  CAS  Google Scholar 

  • Funchal C, de Almeida LM, Oliveira Loureiro S, Vivian L, de Lima Pelaez P, Dall Bello Pessutto F, Rosa AM, Wajner M, Pessoa Pureur R (2003) In vitro phosphorylation of cytoskeleton proteins from cerebral cortex of rats. Brain Res. Brain Res Protoc 11:111–118

    Article  PubMed  CAS  Google Scholar 

  • Funchal C, Zamoner A, dos Santos AQ, Loureiro SO, Wajner M, Pessoa-Pureur R (2005a) Alpha-ketoisocaproic acid increases phosphorylation of intermediate filament proteins from rat cerebral cortex by mechanisms involving Ca2+ and cAMP. Neurochem Res 30:1139–1146

    Article  PubMed  CAS  Google Scholar 

  • Funchal C, Zamoner A, dos Santos AQ, Moretto MB, Rocha JB, Wajner M, Pessoa-Pureur R (2005b) Evidence that intracellular Ca2+ mediates the effect of alpha-ketoisocaproic acid on the phosphorylating system of cytoskeletal proteins from cerebral cortex of immature rats. J Neurol Sci 238:75–82

    Article  PubMed  CAS  Google Scholar 

  • Giasson BI, Mushynski WE (1997) Study of proline-directed protein kinases involved in phosphorylation of the heavy neurofilament subunit. J Neurosci 17:9466–9472

    PubMed  CAS  Google Scholar 

  • Gibson KM, Breuer J, Nyhan WL (1988) 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients. Eur J Pediatr 148:180–186

    Article  PubMed  CAS  Google Scholar 

  • Goldstein ME, Sternberger NH, Sternberger LA (1987) Phosphorylation protects neurofilaments against proteolysis. J Neuroimmunol 14:149–160

    Article  PubMed  CAS  Google Scholar 

  • Grant P, Pant HC (2000) Neurofilament protein synthesis and phosphorylation. J Neurocytol 29:843–872

    Article  PubMed  CAS  Google Scholar 

  • Guidato S, Bajaj NP, Miller CC (1996) Cellular phosphorylation of neurofilament heavy-chain by cyclin-dependent kinase-5 masks the epitope for monoclonal antibody N52. Neurosci Lett 217:157–160

    Article  PubMed  CAS  Google Scholar 

  • Heimfarth L, Loureiro SO, Reis KP, de Lima BO, Zamboni F, Lacerda S, Soska AK, Wild L, da Rocha JB, Pessoa-Pureur R (2012a) Diphenyl ditelluride induces hypophosphorylation of intermediate filaments through modulation of DARPP-32-dependent pathways in cerebral cortex of young rats. Arch Toxicol 86:217–230

    Article  PubMed  CAS  Google Scholar 

  • Heimfarth L, Loureiro SO, Dutra MF, Andrade C, Pettenuzzo L, Guma FT, Gonçalves CA, da Rocha JB, Pessoa-Pureur R (2012b) In vivo treatment with diphenyl ditelluride induces neurodegeneration in striatum of young rats: implications of MAPK and Akt pathways. Toxicol Appl Pharmacol 264:143–152

    Article  PubMed  CAS  Google Scholar 

  • Heimfarth L, Loureiro SO, Dutra MF, Petenuzzo L, de Lima BO, Fernandes CG, da Rocha JB, Pessoa-Pureur R (2013a) Disrupted cytoskeletal homeostasis, astrogliosis and apoptotic cell death in the cerebellum of preweaning rats injected with diphenyl ditelluride. Neurotoxicology 34:175–188

    Article  PubMed  CAS  Google Scholar 

  • Heimfarth L, Loureiro SO, Pierozan P, de Lima BO, Reis KP, Torres EB, Pessoa-Pureur R (2013b) Methylglyoxal-induced cytotoxicity in neonatal rat brain: a role for oxidative stress and MAP kinases. Metab Brain Dis 28:429–438

    Article  PubMed  CAS  Google Scholar 

  • Hisanaga S, Gonda Y, Inagaki M, Ikai A, Hirokawa N (1990) Effects of phosphorylation of the neurofilament L protein of filamentous structures. Cell Regul 1:237–248

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kovacic P, Somanathan R (2010) Clinical physiology and mechanism of dizocilpine (MK-801): electron transfer, radicals, redox metabolites and bioactivity. Oxid Med Cell Longev 3:13–22

    Article  PubMed  PubMed Central  Google Scholar 

  • Kowaltowski AJ, Castilho RF, Vercesi AE (2001) Mitochondrial permeability transition and oxidative stress. FEBS Lett 495:12–15

    Article  PubMed  CAS  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  PubMed  CAS  Google Scholar 

  • Lai JC, Cooper AJ (1986) Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors. J Neurochem 47:1376–1386

    Article  PubMed  CAS  Google Scholar 

  • Leipnitz G, Seminotti B, Haubrich J, Dalcin KB, Solano A, de Bortoli G, Rosa RB, Amaral AU, Dutra-Filho CS, Latini A, Wajner M (2008a) Evidence that 3-hydroxy-3-mthylglutaric acid promotes lipid and protein oxidative damage and reduces the nonenzymatic antioxidant defenses in rat cerebral cortex. J Neurosci Res 86:683–693

    Article  PubMed  CAS  Google Scholar 

  • Leipnitz G, Seminotti B, Amaral AU, de Bortoli G, Solano A, Schuck PF, Wyse AT, Wannmacher CM, Latini A, Wajner M (2008b) Induction of oxidative stress by the metabolites accumulating in 3-methylglutaconic aciduria in cerebral cortex of young rats. Life Sci 82:652–662

    Article  PubMed  CAS  Google Scholar 

  • Leipnitz G, Seminotti B, Fernandes CG, Amaral AU, Beskow AP, da Silva LDB, Zanatta A, Ribeiro CA, Vargas CR, Wajner M (2009) Striatum is more vulnerable to oxidative damage induced by the metabolites accumulating in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency as compared to liver. Int J Dev Neurosci 27:351–356

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Peterson DA, Kimura H, Schubert D (1997) Mechanism of cellular 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction. J Neurochem 69:581–593

    Article  PubMed  CAS  Google Scholar 

  • Loureiro SO, Heimfarth L, Lacerda BA, Vidal LF, Soska A, dos Santos NG, de Souza Wyse AT, Pessoa-Pureur R (2010a) Homocysteine induces hypophosphorylation of intermediate filaments and reorganization of actin cytoskeleton in C6 glioma cells. Cell Mol Neurobiol 30:557–568

    Article  PubMed  CAS  Google Scholar 

  • Loureiro SO, Romão L, Alves T, Fonseca A, Heimfarth L, Moura Neto V, Wyse AT, Pessoa-Pureur R (2010b) Homocysteine induces cytoskeletal remodeling and production of reactive oxygen species in cultured cortical astrocytes. Brain Res 1355:151–164

    Article  PubMed  CAS  Google Scholar 

  • Loureiro SO, Heimfarth L, Scherer EB, da Cunha MJ, de Lima BO, Biasibetti H, Pessoa-Pureur R, Wyse AT (2013) Cytoskeleton of cortical astrocytes as a target to proline through oxidative stress mechanisms. Exp Cell Res 319:89–104

    Article  PubMed  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  • Middeldorp J, Hol EM (2011) GFAP in health and disease. Prog Neurobiol 93:421–443

    Article  PubMed  CAS  Google Scholar 

  • Mirandola SR, Melo DR, Schuck PF, Ferreira GC, Wajner M, Castilho RF (2008) Methylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptake. J Inherit Metab Dis 31:44–54

    Article  PubMed  CAS  Google Scholar 

  • Morrison JF (1954) The activation of aconitase by ferrous ions and reducing agents. Biochem J 58:685–692

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Mota SI, Ferreira IL, Pereira C, Oliveira CR, Rego AC (2012) Amyloid-beta peptide 1-42 causes microtubule deregulation through N-methyl-D-aspartate receptors in mature hippocampal cultures. Curr Alzheimer Res 9:844–856

    Article  PubMed  CAS  Google Scholar 

  • Pant HC (1988) Dephosphorylation of neurofilament proteins enhances their susceptibility to degradation by calpain. Biochem J 256:665–668

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Park HS, Huh SH, Kim MS, Lee SH, Choi EJ (2000) Nitric oxide negatively regulates c-JunN-terminalkinase/stress-activated protein kinase by means of S-nitrosylation. Proc Natl Acad Sci USA 97:14382–14387

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Perrot R, Eyer J (2009) Neuronal intermediate filaments and neurodegenerative disorders. Brain Res Bull 80:282–295

    Article  PubMed  CAS  Google Scholar 

  • Pié J, López-Viñas E, Puisac B, Menao S, Pie A, Casale C, Ramos FJ, Hegardt FG, Gómez-Puertas P, Casals N (2007) Molecular genetics of HMG-CoA lyase deficiency. Mol Genet Metab 92:198–229

    Article  PubMed  Google Scholar 

  • Pierozan P, Zamoner A, Soska AK, Silvestrin RB, Loureiro SO, Heimfarth L, Mello e Souza T, Wajner M, Pessoa-Pureur R (2010) Acute intrastriatal administration of quinolinic acid provokes hyperphosphorylation of cytoskeletal intermediate filament proteins in astrocytes and neurons of rats. Exp Neurol 224:188–196

    Article  PubMed  CAS  Google Scholar 

  • Pierozan P, Zamoner A, Soska ÂK, de Lima BO, Reis KP, Zamboni F, Wajner M, Pessoa-Pureur R (2012) Signaling mechanisms downstream of quinolinic acid targeting the cytoskeleton of rat striatal neurons and astrocytes. Exp Neurol 233:391–399

    Article  PubMed  CAS  Google Scholar 

  • Pierozan P, Gonçalves Fernandes C, Ferreira F, Pessoa-Pureur R (2014) Acute intrastriatal injection of quinolinic acid provokes long-lasting misregulation of the cytoskeleton in the striatum, cerebral cortex and hippocampus of young rats. Brain Res 1577:1–10

    Article  PubMed  CAS  Google Scholar 

  • Reimão S, Morgado C, Almeida IT, Silva M, Corte Real H, Campos J (2009) 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: initial presentation in a young adult. J Inherit Metab Dis 32:S49–S52

    Article  PubMed  Google Scholar 

  • Reis de Assis D, RdeC Maria, Borba Rosa R, Schuck PF, Ribeiro CA, da Costa Ferreira G, Dutra-Filho CS, de Souza Terezinha, Wyse A, Duval Wannmacher CM, Santos Perry ML, Wajner M (2004) Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency. Brain Res 1030:141–151

    Article  PubMed  CAS  Google Scholar 

  • Ribeiro CA, Hickmann FH, Wajner M (2011) Neurochemical evidence that 3-methylglutaric acid inhibits synaptic Na + , K + -ATPase activity probably trough oxidative damage in brain cortex of young rats. Int J Dev Neurosci 29:1–7

    Article  PubMed  CAS  Google Scholar 

  • Rittase WB, Dong Y, Barksdale D, Galdzicki Z, Bausch SB (2014) Dynorphin up-regulation in the dentate granule cell mossy fiber pathway following chronic inhibition of GluN2B-containing NMDAR is associated with increased CREB (Ser 133) phosphorylation, but is independent of BDNF/TrkB signaling pathways. Mol Cell Neurosci 60:63–71

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Rosenthal RE, Hamud F, Fiskum G, Varghese PJ, Sharpe S (1987) Cerebral ischemia and reperfusion: prevention of brain mitochondrial injury by lidoflazine. J Cereb Blood Flow Metab 7:752–758

    Article  PubMed  CAS  Google Scholar 

  • Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray JM, Munnich A (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228:35–51

    Article  PubMed  CAS  Google Scholar 

  • Sheppeck JE, Gauss CM, Chamberlin AR (1997) Inhibition of the Ser-Thr phosphatases PP1 and PP2A by naturally occurring toxins. Bioorg Med Chem 5:1739–1750

    Article  PubMed  CAS  Google Scholar 

  • Sihag RK, Nixon RA (1989) In vivo phosphorylation of distinct domains of the 70-kilodalton neurofilament subunit involves different protein kinases. J Biol Chem 264:457–464

    PubMed  CAS  Google Scholar 

  • Sihag RK, Inagaki M, Yamaguchi T, Shea TB, Pant HC (2007) Role of phosphorylation on the structural dynamics and function of types III and IV intermediate filaments. Exp Cell Res 313:2098–2109

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Strack S, Westphal RS, Colbran RJ, Ebner FF, Wadzinski BE (1997) Protein serine/threonine phosphatase 1 and 2A associate with and dephosphorylate neurofilaments. Brain Res Mol Brain Res 49:15–28

    Article  PubMed  CAS  Google Scholar 

  • Sweetman L, Wlliams JC (2001) Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 2340–2342

    Google Scholar 

  • Tretter L, Adam-Vizi V (2000) Inhibition of Krebs cycle enzymes by hydrogen peroxide: a key role of [alpha]-ketoglutarate dehydrogenase in limiting NADH production under oxidative stress. J Neurosci 20:8972–8979

    PubMed  CAS  Google Scholar 

  • van der Knaap MS, Bakker HD, Valk J (1998) MR imaging and proton spectroscopy in 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency. AJNR Am J Neuroradiol 19:378–382

    PubMed  Google Scholar 

  • Veeranna GJ, Amin ND, Ahn NG, Jaffe H, Winters CA, Grant P, Pant HC (1998) Mitogen-activated protein kinases (Erk1,2) phosphorylate lys-ser-pro (KSP) repeats in neurofilament proteins NF-H and NF-M. J Neurosci 18:4008–4021

    PubMed  CAS  Google Scholar 

  • Veeranna GJ, Shetty KT, Takahashi M, Grant P, Pant HC (2000) Cdk5 and MAPK are associated with complexes of cytoskeletal proteins in rat brain. Brain Res Mol Brain Res 76:229–236

    Article  PubMed  CAS  Google Scholar 

  • Viegas CM, Zanatta Â, Knebel LA, Schuck PF, Tonin AM, GdaC Ferreira, Amaral AU, Dutra Filho CS, Wannmacher CM, Wajner M (2009) Experimental evidence that ornithine and homocitrulline disrupt energy metabolism in brain of young rats. Brain Res 1291:102–112

    Article  PubMed  CAS  Google Scholar 

  • Whitaker AN, McKay DG (1969) Studies of catecholamine shock. I. Disseminated intravascular coagulation. Am J Pathol 65:153–176

    Google Scholar 

  • Wysocki SJ, Hähnel R (1986) 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: a review. J Inherit Metab Dis 9:225–233

    Article  PubMed  CAS  Google Scholar 

  • Yalçinkaya C, Dinçer A, Gündüz E, Fiçicioğlu C, Koçer N, Aydin A (1999) MRI and MRS in HMG-CoA lyase deficiency. Pediatr Neurol 20:375–380

    Article  PubMed  Google Scholar 

  • Yýlmaz Y, Ozdemir N, Ekinci G, Baykal T, Kocaman C (2006) Corticospinal tract involvement in a patient with 3-HMG coenzyme A lyase deficiency. Pediatr Neurol 35:139–141

    Article  PubMed  Google Scholar 

  • Zafeiriou DI, Augoustides-Savvopoulou P, Haas D, Smet J, Triantafyllou P, Vargiami E, Tamiolaki M, Gombakis N, van Coster R, Sewell AC, Vianey-Saban C, Gregersen N (2007) Ethylmalonic encephalopathy: clinical and biochemical observations. Neuropediatrics 38:78–82

    Article  PubMed  CAS  Google Scholar 

  • Zamoner A, Pierozan P, Vidal LF, Lacerda BA, Dos Santos NG, Vanzin CS, Pessoa-Pureur R (2008a) Vimentin phosphorylation as a target of cell signaling mechanisms induced by 1α,25-dihydroxyvitamin D3 in immature rat testes. Steroids 73:1400–1408

    Article  PubMed  CAS  Google Scholar 

  • Zamoner A, Barreto KP, Filho DW, Sell F, Woehl VM, Guma FC, Pessoa-Pureur R, Silva FR (2008b) Propylthiouracil-induced congenital hypothyroidism upregulates vimentin phosphorylation and depletes antioxidant defenses in immature rat testis. J Mol Endocrinol 40:125–135

    Article  PubMed  CAS  Google Scholar 

  • Zhou X, Ding Q, Chen Z, Yun H, Wang H (2013a) Involvement of the GluN2A and GluN2B subunits in synaptic and extrasynaptic N-methyl-D-aspartate receptor function and neuronal excitotoxicity. J Biol Chem 288:24151–24159

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zhou X, Hollern D, Liao J, Andrechek E, Wang H (2013b) NMDA receptor-mediated excitotoxicity depends on the coactivation of synaptic and extrasynaptic receptors. Cell Death Dis 4:e560

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by Grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, # 470236/2012-4), Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS, # 10/0031-1), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, # 2011/50400-0), Pró-Reitoria de Pesquisa/Universidade Federal do Rio Grande do Sul (PROPESQ/UFRGS, # PIBITI 18489), Rede Instituto Brasileiro de Neurociência (IBN-Net) (# 01.06.0842-00) and Instituto Nacional de Ciência e Tecnologia em Excitotoxicidade e Neuroproteção (INCT-EN, # 573677/2008-5).

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  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600 anexo, Porto Alegre, RS, CEP 90035-003, Brazil

    Carolina Gonçalves Fernandes, Paula Pierozan, Gilberto Machado Soares, Fernanda Ferreira, Ângela Zanatta, Alexandre Umpierrez Amaral, Clarissa Günther Borges, Moacir Wajner & Regina Pessoa-Pureur

  2. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Moacir Wajner

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  1. Carolina Gonçalves Fernandes
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Fernandes, C.G., Pierozan, P., Soares, G.M. et al. NMDA Receptors and Oxidative Stress Induced by the Major Metabolites Accumulating in HMG Lyase Deficiency Mediate Hypophosphorylation of Cytoskeletal Proteins in Brain From Adolescent Rats: Potential Mechanisms Contributing to the Neuropathology of This Disease. Neurotox Res 28, 239–252 (2015). https://doi.org/10.1007/s12640-015-9542-z

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