Original article| Volume 27, ISSUE 1, P34-38, January 2005

Download started.


Oxidative nucleotide damage and superoxide dismutase expression in the brains of xeroderma pigmentosum group A and Cockayne syndrome


      Xeroderma pigmentosum group A (XPA) and Cockayne syndrome (CS) are caused by a genetic defect of nucleotide excision repair mechanisms, showing cutaneous hypersensitivity to sunlight and progressive neurological disturbances. The cause of neurological abnormalities has yet to be clarified and fundamental treatments have never been established in both disorders. In order to investigate neurodegeneration of XPA and CS, we immunohistochemically examined deposition of oxidative stress-related materials of nucleotides and expression of two types of superoxide dismutase (SOD) in the brains from autopsy cases of XPA and CS. Cases of XPA but not CS demonstrated nuclear deposition of 8-hydroxy-2′-deoxyguanosine and cytoplasmic deposition of 8-hydroxyguanosine, being speculated as oxidative stress-related materials of DNA and RNA, respectively, in the globus pallidus. Four of five XPA cases exhibited reduced neuronal immunoreactivity for Cu/ZnSOD in the cerebral and cerebellar corteces in addition to the basal ganglia, and two XPA cases showed reduced immunoreactivity for MnSOD in the brain regions examined. In contrast, five CS cases demonstrated comparatively preserved immunoreactivity for Cu/ZnSOD and MnSOD. Both XPA and CS cases showed increased cytoplasmic immunoreactivity for Cu/ZnSOD and/or MnSOD in the microglial cells in the cerebral and cerebellar white matters. These findings suggest that oxidative damage to nucleotides and disturbed SOD expression can be involved in neurodegeneration in XPA but not CS.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bootsma D.
        • Kraemer K.H.
        • Cleaver J.E.
        • Hoeijmakers J.H.
        Scriber C.R. Beaudet A.L. Sly W.S. Valle D. Nucleotide excision repair syndromes: xeroderma pigmentosum Cockayne syndrome, and trichothiodystrophy. 8th ed. The metabolic and molecular bases of inherited disease. vol. I. McGraw-Hill, New York2001: 677-703
        • Kohji T.
        • Hayashi M.
        • Shioda K.
        • Minagawa M.
        • Morimatsu Y.
        • Tamagawa K.
        • et al.
        Cerebellar neurodegeneration in human hereditary DNA repair disorders.
        Neurosci Lett. 1998; 243: 133-136
        • Itoh M.
        • Hayashi M.
        • Shioda K.
        • Minagawa M.
        • Isa F.
        • Tamagawa K.
        • et al.
        Neurodegeneration in hereditary nucleotide repair disorders.
        Brain Dev. 1999; 21: 326-333
        • Hayashi M.
        • Itoh M.
        • Araki S.
        • Kumada S.
        • Shioda K.
        • Tamagawa K.
        • et al.
        Oxidative stress and disturbed glutamate transport in hereditary nucleotide repair disorders.
        J Neuropathol Exp Neurol. 2001; 60: 350-356
        • Bogdanov M.
        • Brown Jr., R.H.
        • Matson W.
        • Smart R.
        • Hayden D.
        • O'Donnel H.
        • et al.
        Increased oxidative damage to DNA in ALS patients.
        Free Radic Biol Med. 2000; 29: 652-658
        • Nunomura A.
        • Perry G.
        • Aliev G.
        • Hirai K.
        • Takeda A.
        • Balraj E.K.
        • et al.
        Oxidative damage is the earliest event in Alzheimer disease.
        J Neuropathol Exp Neurol. 2001; 60: 759-767
        • Kikuchi A.
        • Takeda A.
        • Onodera H.
        • Kimpara T.
        • Hisanaga K.
        • Sato N.
        • et al.
        Systemic increase of oxidative nucleic acid damage in Parkinson's disease and multiple system atrophy.
        Neurobiol Dis. 2002; 9: 244-248
        • Hayashi M.
        • Arai N.
        • Satoh J.
        • Suzuki H.
        • Katayama K.
        • Tamagawa K.
        • et al.
        Neurodegenerative mechanisms in subacute sclerosing panencephalitis.
        J Child Neurol. 2002; 17: 725-730
        • Hayashi M.
        • Araki S.
        • Arai N.
        • Kumada S.
        • Itoh M.
        • Tamagawa K.
        • et al.
        Oxidative stress and disturbed glutamate transport in spinal muscular atrophy.
        Brain Dev. 2002; 24: 770-775
        • Araki S.
        • Hayashi M.
        • Tamagawa K.
        • Saito M.
        • Kato S.
        • Komori T.
        • et al.
        Neuropathological analysis in spinal muscular atrophy type II.
        Acta Neuropathol. 2003; 106: 441-448
        • Fridovich I.
        Superoxide radical and superoxide dismutases.
        Annu Rev Biochem. 1995; 64: 97-112
        • Furuta A.
        • Price D.L.
        • Pardo C.A.
        • Toroncoso J.C.
        • Xu Z.S.
        • Taniguchi N.
        • et al.
        Localization of superoxide dismutases in Alzheimer's disease and Down's syndrome neocortex and hippocampus.
        Am J Pathol. 1995; 146: 357-367
        • Shibata N.
        • Hirano A.
        • Kobayashi M.
        • Umehara T.
        • Kawanami T.
        • Asayama K.
        Cerebellar superoxide dismutase expression in Menkes' kinky hair disease: an immunohistochemical investigation.
        Acta Neuropathol. 1995; 90: 198-202
        • Cantuti-Castelverti I.
        • Keller-McGandy C.E.
        • Albers D.S.
        • Beal M.F.
        • Vonsattel J.P.
        • Standaert D.G.
        • et al.
        Expression and activity of antioxidants in the brain in progressive supranuclear palsy.
        Brain Res. 2002; 930: 170-181
        • Toyokuni S.
        • Tanaka T.
        • Hattori Y.
        • Nishiyama Y.
        • Yoshida A.
        • Uchida K.
        • et al.
        Quantitative immunohistochemical determination of 8-hydroxy-2′-deoxyguanosine by a monoclonal antibody N45.1: its application to ferric nitrilotriacetate-induced renal carcinogenesis model.
        Lab Invest. 1997; 76: 365-374
        • Simonian N.A.
        • Coyle J.T.
        Oxidative stress in neurodegenerative diseases.
        Annu Rev Pharmacol Toxicol. 1996; 36: 83-106
        • Tuo J.
        • Jaruga P.
        • Rodrigue H.
        • Bohr V.A.
        • Dizdaroglu M.
        Primary fibroblast of Cockayne syndrome patients are defective in cellular repair of 8-hydroxyguanine and 8-hydroxyadenine resulting from oxidative stress.
        Fed Am Soc Exp Biol J. 2003; 17: 668-674
        • Le Page F.
        • Kwoh E.E.
        • Avrutskaya A.
        • Gentil A.
        • Leadon S.A.
        • Sarasin A.
        • et al.
        Transcription-coupled repair of 8-oxoguanine: requirement for XPG, TFIIH, and CSB and implication for Cockayne syndrome.
        Cell. 2000; 101: 159-171
        • de Waard H.
        • de Wit J.
        • Gorgels T.G.M.F.
        • van den Aardweg G.
        • Andressoo J.O.
        • Vermeij M.
        • et al.
        Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice.
        DNA Repair. 2003; 2: 13-25
        • Reardon J.T.
        • Bessho T.
        • Kung H.C.
        • Bolton P.H.
        • Sancer A.
        In vitro repair of oxidative DNA damage by human nucleotide excision repair system: possible explanation for neurodegeneration in xeroderma pigmentosum patients.
        Proc Natl Acad Sci USA. 1997; 94: 9463-9468
        • Cardozo-Pelaez F.
        • Brooks P.J.
        • Stedeford T.
        • Song S.
        • Sanchez-Ramos J.
        DNA damage, repair, and antioxidant systems in brain regions: a correlative study.
        Free Radic Biol Med. 2000; 28: 779-785
        • Schallreuter K.U.
        • Pittelkow M.R.
        • Wood J.M.
        Defects in antioxidant defense and calcium transport in the epidermis of xeroderm pigmentosu patients.
        Arch Dermatol. 1991; 283: 449-455
        • Vuillaume M.
        • Daya-Grosjean L.
        • Vincens P.
        • Penneitier J.L.
        • Tarroux P.
        • Baret A.
        • et al.
        Striking differences in cellular catalase activity between two DNA repair-deficient diseases: xeroderma pigmentosum and trichothiodystrophy.
        Carcinogenesis. 1992; 13: 321-328
        • Hoffschir F.
        • Daya-Grosjean L.
        • Petit P.X.
        • Nocentini S.
        • Dutrillaux B.
        • Sarasin A.
        • et al.
        Low catalase activity in xeroderma pigmentosum fibroblasts and SV40-transformed human cell lines is directly related to decreased intracellular levels of the cofactor NADPH.
        Free Radic Biol Med. 1998; 24: 809-816