A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration

Gabriele De Luca, Maria Teresa Russo, Paolo Degan, Cecilia Tiveron, Andrea Zijno, Ettore Meccia, Ilenia Ventura, Elisabetta Mattei, Yusaku Nakabeppu, Marco Crescenzi, Rita Pepponi, Antonella Pèzzola, Patrizia Popoli, Margherita Bignami

研究成果: ジャーナルへの寄稿記事

47 引用 (Scopus)

抄録

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.

元の言語英語
記事番号e1000266
ジャーナルPLoS Genetics
4
発行部数11
DOI
出版物ステータス出版済み - 11 1 2008

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Corpus Striatum
Huntington Disease
Nucleic Acid Precursors
nucleosides
hydrolases
DNA
nucleic acids
signs and symptoms (animals and humans)
mice
3-nitropropionic acid
nucleic acid
Hydrolases
disease models
guanine
neurodegenerative diseases
gait
purines
Purine Nucleosides
oxidants
Behavioral Symptoms

All Science Journal Classification (ASJC) codes

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

これを引用

De Luca, G., Russo, M. T., Degan, P., Tiveron, C., Zijno, A., Meccia, E., ... Bignami, M. (2008). A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration. PLoS Genetics, 4(11), [e1000266]. https://doi.org/10.1371/journal.pgen.1000266

A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration. / De Luca, Gabriele; Russo, Maria Teresa; Degan, Paolo; Tiveron, Cecilia; Zijno, Andrea; Meccia, Ettore; Ventura, Ilenia; Mattei, Elisabetta; Nakabeppu, Yusaku; Crescenzi, Marco; Pepponi, Rita; Pèzzola, Antonella; Popoli, Patrizia; Bignami, Margherita.

:: PLoS Genetics, 巻 4, 番号 11, e1000266, 01.11.2008.

研究成果: ジャーナルへの寄稿記事

De Luca, G, Russo, MT, Degan, P, Tiveron, C, Zijno, A, Meccia, E, Ventura, I, Mattei, E, Nakabeppu, Y, Crescenzi, M, Pepponi, R, Pèzzola, A, Popoli, P & Bignami, M 2008, 'A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration', PLoS Genetics, 巻. 4, 番号 11, e1000266. https://doi.org/10.1371/journal.pgen.1000266
De Luca G, Russo MT, Degan P, Tiveron C, Zijno A, Meccia E その他. A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration. PLoS Genetics. 2008 11 1;4(11). e1000266. https://doi.org/10.1371/journal.pgen.1000266
De Luca, Gabriele ; Russo, Maria Teresa ; Degan, Paolo ; Tiveron, Cecilia ; Zijno, Andrea ; Meccia, Ettore ; Ventura, Ilenia ; Mattei, Elisabetta ; Nakabeppu, Yusaku ; Crescenzi, Marco ; Pepponi, Rita ; Pèzzola, Antonella ; Popoli, Patrizia ; Bignami, Margherita. / A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration. :: PLoS Genetics. 2008 ; 巻 4, 番号 11.
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