Neurochemical Research

, Volume 31, Issue 9, pp 1103–1109

Oxidative Stress in Skin Fibroblasts Cultures of Patients with Huntington’s Disease

  • Pilar del Hoyo
  • Alberto García-Redondo
  • Fernando de Bustos
  • José Antonio Molina
  • Youssef Sayed
  • Hortensia Alonso-Navarro
  • Luis Caballero
  • Joaquín Arenas
  • Félix Javier Jiménez-Jiménez
Original Paper

Abstract

Oxidative stress and mitochondrial dysfunction should play a role in the neurodegeneration in Huntington’s disease (HD). The most consistent finding is decreased activity of the mitochondrial complexes II/III and IV of the respiratory chain in the striatum. We assessed enzymatic activities of respiratory chain enzymes and other enzymes involved in oxidative processes in skin fibroblasts cultures of patients with HD.

We studied respiratory chain enzyme activities, activities of total, Cu/Zn- and Mn-superoxide-dismutase, glutathione-peroxidase (GPx) and catalase, and coenzyme Q10 (CoQ10) levels in skin fibroblasts cultures from 13 HD patients and 13 age- and sex-matched healthy controls.

When compared with controls, HD patients showed significantly lower specific activities for catalase corrected by protein concentrations (P < 0.01). Oxidized, reduced and total CoQ10 levels (both corrected by citrate synthase (CS) and protein concentrations), and activities of total, Cu/Zn- and Mn-superoxide-dismutase, and gluthatione-peroxidase, did not differ significantly between HD-patients and control groups. Values for enzyme activities in the HD group did not correlate with age at onset and of the disease and with the CAG triplet repeats.

The primary finding of this study was the decreased activity of catalase in HD patients, suggesting a possible contribution of catalase, but not of other enzymes related with oxidative stress, to the pathogenesis of this disease.

Keywords

Huntington’ disease Oxidative stress Mitochondrial respiratory chain Glutathione-peroxidase Superoxide-dismutase Coenzyme Q10 Catalase Etiopathogenesis 

References

  1. 1.
    Gusella JF, MacDonald ME (1997) Genetics and molecular biology of Huntington’s disease. In: Watts RL, Koller WC (eds) Movement disorders: neurologic principles and practice. McGraw-Hill, New-York, pp 477–490Google Scholar
  2. 2.
    Calopa-Garriga M, Genís-Battle D, Sánchez-Díaz A (1998) Enfermedad de Huntington. In: Jiménez-Jiménez FJ, Luquin MR, Molina JA (eds) Tratado de los trastornos del movimiento. IM&C, Madrid, pp 725–760Google Scholar
  3. 3.
    Biglan KM, Shoulson I (2002) Huntington’s disease. In: Jankovic JJ, Tolosa E (eds) Parkinson’s disease and movement disorders, 4th edn. Lippincott Williams & Wilkins, Philadelphia, pp 212–227Google Scholar
  4. 4.
    Browne SE, Bowling AC, MacGarvey U et al (1997) Oxidative damage and metabolic dysfunction in Huntington’s disease: selective vulnerability of the basal ganglia. Ann Neurol 41:646–653PubMedCrossRefGoogle Scholar
  5. 5.
    Browne SE, Ferrante RJ, Beal MF (1999) Oxidative stress in Huntington’s disease. Brain Pathol 9:147–163PubMedCrossRefGoogle Scholar
  6. 6.
    Bogdanov MB, Andreassen OA, Dedeoglu A et al (2001) Increased oxidative damage in a transgenic mouse model of Huntingtons’s disease. J Neurochem 79:1246–1249PubMedCrossRefGoogle Scholar
  7. 7.
    Pérez-Severiano F, Santamaría A, Pedraza-Chaverri J et al (2004) Increased formation of reactive oxygen species, but no changes in glutathione peroxidase activity, in striata of mice transgenic for the Huntington’s disease mutation. Neurochem Res 29:729–733 PubMedCrossRefGoogle Scholar
  8. 8.
    Rossi SR, Simpson JR, Isacson O (1993) Age dependence of striatal neuronal death caused by mitochondrial dysfunction. Neuroreport 4:73–76CrossRefGoogle Scholar
  9. 9.
    Beal MF, Brouillet E, Jenkins BG et al (1993) Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J Neurosci 13:4181–4192PubMedGoogle Scholar
  10. 10.
    Brouillet E, Hantraye P, Ferrante RJ et al (1995) Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates. Proc Natl Acad Sci USA 92:7105–7109PubMedCrossRefGoogle Scholar
  11. 11.
    Fontaine MA, Geddes JW, Banks A et al (2000) Effect of exogenous and endogenous antioxidants on 3-nitropropionic acid-induced in vivo oxidative stress and striatal lesions: insights into Huntington’s disease. J Neurochem 75:1709–1715PubMedCrossRefGoogle Scholar
  12. 12.
    Túnez I, Drucker-Colin R, Jimena I et al (2006) Transcranial magnetic stimulation attenuates cell loss and oxidative damage in the striatum induced in the 3-nitropropionic model of Huntington’s disease. J Neurochem 97:619–630PubMedCrossRefGoogle Scholar
  13. 13.
    Túnez I, Montilla P, Del Carmen-Muñoz M et al (2004) Protective effect of melatonin on 3-nitropropionic acid-induced oxidative stress in synaptosomes in an animal model of Huntington’s disease. J Pineal Res 37:252–256PubMedCrossRefGoogle Scholar
  14. 14.
    Beal MF, Brouillet E, Jenkins B et al (1993) Age-dependent striatal excitotoxic lesions produced by the endogenous mitochondrial inhibitor malonate. J Neurochem 61:1147–1150PubMedCrossRefGoogle Scholar
  15. 15.
    Schapira AHV (1994) Mitochondrial dysfunction in neurodegenerative disorders and aging. In: Schapira AHV, DiMauro S (eds) Mitochondrial disorders in neurology. Butterworth-Heinemann Ltd., Oxford, 227–244Google Scholar
  16. 16.
    Jiménez-Jiménez FJ, Ortí-Pareja M, Molina JA (1998) Alteraciones mitocondriales en las enfermedades neurodegenerativas. In: Jiménez-Jiménez FJ, Molina JA, Arenas J (eds) Enfermedades mitocondriales. Rev. Neurol. 26 Suppl 1:S 112-S 117Google Scholar
  17. 17.
    Kish SJ, Morito CL, Hornykiewicz O (1986) Brain glutathione peroxidase in neurodegenerative disorders. Neurochem Pathol 4:23–28PubMedGoogle Scholar
  18. 18.
    Loomis TC, Yee G, Stahl WL (1976) Regional and subcellular distribution of superoxide dismutase in brain. Experientia 32:1364–1376CrossRefGoogle Scholar
  19. 19.
    Klivenyi P, Andreassen OA, Ferrante RJ et al (2000) Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. J Neurosci 20:1–7PubMedGoogle Scholar
  20. 20.
    Santamaría A, Pérez-Severiano F, Rodríguez-Martínez E et al (2001) Comparative analysis of superoxide dismutase activity between acute pharmacological models and a transgenic mouse model of Huntington’s disease. Neurochem Res 26:419–424PubMedCrossRefGoogle Scholar
  21. 21.
    Hansson O, Petersen A, Leist M et al (1999) Transgenic mice expressing a Huntington’s disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. Proc Natl Acad Sci USA 96:8727–8732PubMedCrossRefGoogle Scholar
  22. 22.
    Ernster L, Dallner G (1995) Biochemical, physiological and medical aspects of ubiquinone function. Ann Neurol 42:261–264Google Scholar
  23. 23.
    Shults CQ, Haas RH, Passov D et al (1997) Coenzyme Q10 levels correlate with the activities of complexes I and II/III mitochondria from parkinsonian and nonparkinsonian patients. Ann Neurol 42:261–264PubMedCrossRefGoogle Scholar
  24. 24.
    Andrich J, Saft C, Gerlach M et al (2004) Coenzyme Q10 serum levels in Huntington’s disease. J Neural Transm 68:111–116Google Scholar
  25. 25.
    Barroso N, Campos Y, Huertas R et al (1993) Respiratory chain enzyme activities in lymphocytes from untreated patients with Parkinson disease. Clin Chem 39:667–669PubMedGoogle Scholar
  26. 26.
    Zheng X, Shoffner JM, Voljavec AS et al (1990) Evaluation of procedures for assaying oxidative phosphorylation enzyme activities in mitochondrial myopathy muscle biopsies. Biochim Biophys Acta 101:1–10Google Scholar
  27. 27.
    Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin phenlo reagent. J Biol Chem 193:265–271PubMedGoogle Scholar
  28. 28.
    Flohé L, Günzler W (1984) Assays of glutathione peroxidase. Methods Enzymol 105:114–121PubMedGoogle Scholar
  29. 29.
    Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126PubMedCrossRefGoogle Scholar
  30. 30.
    Spitz DR, Oberley LW (1989) An assay for superoxide dismutase activity in mammalian tissue homogenates. Anal Biochem 179:8–18PubMedCrossRefGoogle Scholar
  31. 31.
    Langedijk J, Ubbink JB, Vermaak WJH (1996) Measurement of the ratio between the reduced and oxidized forms of coenzyme Q10 in human plasma as a possible marker of oxidative stress. J Lipid Res 37:67–75Google Scholar
  32. 32.
    Brennan Jr WA, Bird ED, Aprille JR (1985) Regional mitochondrial respiratory activity in Huntington’s disease brain. J Neurochem 44:1948–1950PubMedCrossRefGoogle Scholar
  33. 33.
    Mann VM, Cooper JM, Javoy-Agid Y et al (1990) Mitochondrial function and parental sex effect in Huntington’s disease. Lancet 336:749PubMedCrossRefGoogle Scholar
  34. 34.
    Gu M, Gash MT, Mann VM et al (1996) Mitochondrial defect in Huntington’s disease caudate nucleus. Ann Neurol 39:385–389PubMedCrossRefGoogle Scholar
  35. 35.
    Tabrizi SJ, Cleeter MW, Xuereb J et al (1999) Biochemical abnormalities and excitotoxicity in Huntington’s disease brain. Ann Neurol 45:25–32PubMedCrossRefGoogle Scholar
  36. 36.
    Parker Jr WD, Boyson SJ, Luder AS, Parks JK et al (1990) Evidence for a defect in NADP: ubiquinone oxidoreductase (complex I) in Huntington’s disease. Neurology 40:1231–1234PubMedGoogle Scholar
  37. 37.
    Arenas J, Campos Y, Ribacoba R et al (1998) Complex I defect in muscle from patients with Huntington’s disease. Ann Neurol 43:397–400PubMedCrossRefGoogle Scholar
  38. 38.
    Panov AV, Gutekunst CA, Leavitt BR et al (2002) Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat Neurosci 5:731–736PubMedGoogle Scholar
  39. 39.
    Koroshetz WJ, Jenkins BG, Rosen BR et al (1997) Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann Neurol 41:160–165PubMedCrossRefGoogle Scholar
  40. 40.
    Lodi R, Schapira AH, Manners D et al (2000) Abnormal in vivo skeletal muscle energy metabolism in Huntington’s disease and dentatorubropallidoluysian atrophy. Ann Neurol 48:72–76PubMedCrossRefGoogle Scholar
  41. 41.
    Schilling G, Coonfield ML, Ross CA et al (2001) Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington’s disease transgenic mouse model. Neurosci Lett 315:149–153PubMedCrossRefGoogle Scholar
  42. 42.
    Schilling G, Savonenko AV, Coonfield ML et al (2004) Environmental, pharmacological, and genetic modulation of the HD phenotype in transgenic mice. Exp Neurol 187:137–149PubMedCrossRefGoogle Scholar
  43. 43.
    Feigin A, Kieburtz K, Como P et al (1996) Assessment of coenzyme Q10 tolerability in Huntington’s disease. Mov Disord 11:321–323PubMedCrossRefGoogle Scholar
  44. 44.
    Huntington Study Group (2001) A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 57:397–404Google Scholar
  45. 45.
    Kahl R, Kampkotter A, Watjen W et al (2004) Antioxidant enzymes and apoptosis. Drug Metab Rev 36:747–762PubMedCrossRefGoogle Scholar
  46. 46.
    Okuda S, Nishiyama N, Saito H et al (1996) Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. Proc Natl Acad Sci USA 93:12553–12558PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Pilar del Hoyo
    • 1
  • Alberto García-Redondo
    • 1
  • Fernando de Bustos
    • 2
  • José Antonio Molina
    • 3
  • Youssef Sayed
    • 4
  • Hortensia Alonso-Navarro
    • 4
  • Luis Caballero
    • 2
  • Joaquín Arenas
    • 1
  • Félix Javier Jiménez-Jiménez
    • 4
    • 5
  1. 1.Departamento de Bioquímica—InvestigaciónHospital Universitario Doce de OctubreMadridSpain
  2. 2.Servicio de Bioquímica, Hospital Nuestra Señora del PradoTalavera de la ReinaToledoSpain
  3. 3.Servicio de NeurologíaHospital Universitario Doce de OctubreMadridSpain
  4. 4.Departamento de Medicina-Neurología, Hospital “Príncipe de Asturias”Universidad de Alcalá, Alcalá de HenaresMadridSpain
  5. 5.MadridSpain

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