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学術誌査読

59 被引用数 (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.

本文言語英語
論文番号e1000266
ジャーナルPLoS genetics
4
11
DOI
出版ステータス出版済み - 11月 2008

!!!All Science Journal Classification (ASJC) codes

  • 生態、進化、行動および分類学
  • 分子生物学
  • 遺伝学
  • 遺伝学(臨床)
  • 癌研究

フィンガープリント

「A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル