A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration (Articolo in rivista)

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  • A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration (Articolo in rivista) (literal)
Anno
  • 2008-01-01T00:00:00+01:00 (literal)
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  • De Luca G. 1#; Russo M.T. 1#; Degan P. 2; Tiveron C. 3; Zijno A. 1; Meccia E. 1; Ventura I. 1; Mattei E. 4; Nakabeppu Y. 5; Crescenzi M. 1; Pepponi R. 6; Pezzola A. 6; Popoli P. 6; Bignami M. 1. (2008)
    A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration
    in PLOS genetics; PUBLIC LIBRARY OF SCIENCE, SAN FRANCISCO (Stati Uniti d'America)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • De Luca G. 1#; Russo M.T. 1#; Degan P. 2; Tiveron C. 3; Zijno A. 1; Meccia E. 1; Ventura I. 1; Mattei E. 4; Nakabeppu Y. 5; Crescenzi M. 1; Pepponi R. 6; Pezzola A. 6; Popoli P. 6; Bignami M. 1. (literal)
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  • 14 (literal)
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  • 1 - Department of Environment and Primary Prevention, Experimental Carcinogenesis Division, Istituto Superiore di Sanità, Rome, Italy; 2 - Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro (IST-CBA), Genova, Italy; 3 - European Brain Research Institute, Rome, Italy; 4 - Institute of Neurobiology and Molecular Medicine, CNR, Rome, Italy; 5 - Division of Neurofunctional Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; 6 - Department of Drug Research and Evaluation, Central Nervous System Pharmacology Division, Istituto Superiore di Sanità, Rome, Italy. # These authors contributed equally to this work. (literal)
Titolo
  • A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration (literal)
Abstract
  • The oxidized purine 8-oxo-7,8-dihydroguanine (8-oxodG) is often found at high levels in DNA of post-mortem brains of patients afflicted by Huntington's disease (HD) and other neurodegenerative conditions. It has been unclear, however, whether this damage accumulation is a consequence or a cause of neurodegeneration. We have addressed this problem in a transgenic mouse model in which the human hMTH1 8-oxodGTPase, which hydrolyzes oxidized nucleoside triphosphates to prevent the incorporation of oxidized bases into nucleic acids, was expressed in several organs. We report that high-level hMTH1 expression in the transgenic mouse brain provides robust protection against neurodegeneration as well as HD-like behavioural and neuropathological symptoms in a chemical model of HD (the mitochondrial toxin 3-nitropropionic acid). In a complementary approach, we used a genetic model for HD based on the use of progenitor striatal cells containing an expanded CAG repeat of the huntingtin gene. Also, in this case, hMTH1 provided strong protection against cell death associated with expression of the mutant huntingtin protein. The new findings we report shed important light on the connection between oxidative DNA damage and human neurodegenerative disorders. Our findings go some way towards forging a causative link between neurodegeneration and oxidative DNA/RNA damage and identify the oxidized purine nucleoside triphosphates as important contributors. (literal)
  • Several human neurodegenerative disorders are characterized by the accumulation of 8-oxo-7,8-dihydroguanine (8-oxodG) in the DNA of affected neurons. This can occur either through direct oxidation of DNA guanine or via incorporation of the oxidized nucleotide during replication. Hydrolases that degrade oxidized purine nucleoside triphosphates normally minimize this incorporation. hMTH1 is the major human hydrolase. It degrades both 8-oxodGTP and 8-oxoGTP to the corresponding monophosphates. To investigate whether the incorporation of oxidized nucleic acid precursors contributes to neurodegeneration, we constructed a transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed. hMTH1 expression protected embryonic fibroblasts and mouse tissues against the effects of oxidants. Wild-type mice exposed to 3-nitropropionic acid develop neuropathological and behavioural symptoms that resemble those of Huntington's disease. hMTH1 transgene expression conferred a dramatic protection against these Huntington's disease-like symptoms, including weight loss, dystonia and gait abnormalities, striatal degeneration, and death. In a complementary approach, an in vitro genetic model for Huntington's disease was also used. hMTH1 expression protected progenitor striatal cells containing an expanded CAG repeat of the huntingtin gene from toxicity associated with expression of the mutant huntingtin. The findings implicate oxidized nucleic acid precursors in the neuropathological features of Huntington's disease and identify the utilization of oxidized nucleoside triphosphates by striatal cells as a significant contributor to the pathogenesis of this disorder. (literal)
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