酸化的DNA損傷によるドパミン神経変性とその防御機構の研究

• Project/Area Number: 05F05493
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 外国
• Research Field: Experimental pathology
• Research Institution: Kyushu University
• Principal Investigator: 中別府 雄作 Kyushu University, 生体防御医学研究所, 教授
• Co-Investigator(Kenkyū-buntansha): SHENG Z. 九州大学, 生体防御医学研究所, 外国人特別研究員 ; SHENG Zijing 九州大学, 生体防御医学研究所, 外国人特別研究員
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥2,400,000 (Direct Cost: ¥2,400,000); Fiscal Year 2007: ¥500,000 (Direct Cost: ¥500,000); Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000)
• Keywords: 酸化ストレス / 8-オキソグアニン / 線条体 / OGG1 / MTH1 / MUTYH / ノックアウトマウス / 3-ニトロプロピオン酸 / トランスジェニックマウス / MPTP / 8-oxoguanine / ドパミン神経 / 細胞死 / パーキンソン病

Research Abstract

外国人特別研究員の盛子敬は、3-ニトロプロピオン酸(3-NP)による線条体変性の機序を明らかにする目的で、腹腔内に埋め込んだ浸透圧ポンプで3-NPを慢性投与した野生型マウスの生存率、運動機能、そして脳における8-oxoGの蓄積を詳細に解析した.その結果,3-NP投与開始から4日目から死亡するマウスが出現し、1週間後に約35-40%のマウスが死亡した。運動機能の低下も4日頃から顕著になり、投与1週間後にはロタロッドテストで80%までの運動機能低下が観察された。オープンフィールドにおける総運動距離もコントロールの30%レベルまで低下することが観察された。投与1週間後のマウス脳における8-oxoGの蓄積を免疫染色法で検討したところ、神経細胞の脱落とミクログリアの増生がみられる線条体でのみ顕著な8-oxoGの蓄積が観察された。8-oxoGは線条体の中型有棘神経細胞の核とミトコンドリアの両方に蓄積しており、TH陽性のドパミン神経終末では蓄積は見られなかった。MTH1/OGG1二重欠損マウスに3-NPを投与すると野生型に比べて顕著な行動量の低下を認め,線条体有棘神経細胞の核とミトコンドリアに8-oxoGが著明に蓄積し,神経細胞の脱落を引き起すことが明らかになった。

Research Products

• [Journal Article] Oxidation of mitochondrial deoxynucleotide pools by exposure to sodium nitroprusside induces cell death. (2008)
  • Author(s): Ichikawa J., et. al.
  • Journal Title: DNA Repair 7(3) Pages: 418-430
  • Peer Reviewed
• [Journal Article] Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs. (2008)
  • Author(s): Oka S., et. al.
  • Journal Title: EMBO J. 27(2) Pages: 421-432
  • Peer Reviewed
• [Journal Article] Oxidative damage in nucleic acids and Parkinson's disease. (2007)
  • Author(s): Nakabeppu Y., et. al.
  • Journal Title: J Neurosci Res. 85(5) Pages: 919-934
  • Peer Reviewed
• [Journal Article] RNA Polymerase II bypasses 8-oxoguanine in the presence of transcription elongation factor TFllS. (2007)
  • Author(s): Kuraoka I., Suzuki K., Ito S., Hayashida M., Seah J., Kwei M., Ikegami T., Handa H., Nakabeppu Y., Tanaka K.
  • Journal Title: DNA Repair (印刷中)
• [Journal Article] Accumulation of 8-oxo-deoxyguanosine in Cardiovascular Tissues with the Development of Hypertension. (2007)
  • Author(s): Ohtsubo T., Ohya Y., Nakamura Y., Kansui Y., Furuichi M., Matsumura K., Fujii K., Iida M., Nakabeppu Y.
  • Journal Title: DNA Repair (印刷中)
• [Journal Article] Significance of error-avoiding mechanisms for oxidative DNA damage in carcinogenesis. (2007)
  • Author(s): Tsuzuki T., Nakatsu Y., Nakabeppu Y.
  • Journal Title: Cancer Sci (印刷中)
• [Journal Article] Oxidative Damage in Nucleic Acids and Parkinson's Disease. (2007)
  • Author(s): Nakabeppu Y., Tsuchimoto D., Yamaguchi H., Sakumi K.
  • Journal Title: J.Neurosci.Res. 85・5 Pages: 919-934
• [Journal Article] Induction of apoptosis and cellular senescence in mice lacking transcription elongation factor, Elongin A. (2007)
  • Author(s): Miyata K., Yasukawa T., Fukuda M., Takeuchi T., Yamazaki K., Sakumi K., Tamamori-Adachi M., Ohnishi Y., Ohtsuki Y., Nakabeppu Y., Kitajima S., Onishi S., Aso T.
  • Journal Title: Cell Death Differ. 14・4 Pages: 716-726
• [Journal Article] Recognition of Nucleotide Analogs Containing the 7,8-Dihydro-8-oxo Structure by the Human MTH1 Protein. (2006)
  • Author(s): Kamiya H., Cadena-Amaro C., Dugue L., Yakushiji H., Minakawa N., Matsuda A., Pochet S., Nakabeppu Y., Harashima H.
  • Journal Title: J.Biochem. 140・6 Pages: 843-849
• [Journal Article] Crystallization and preliminary X-ray analysis of human MTH1 complexed with two oxidized nucleotides, 8-oxo-dGMP and 2-oxo-dATP. (2006)
  • Author(s): Nakamura T., Kitaguchi Y., Miyazawa M., Kamiya H., Toma S., Ikemizu S., Shirakawa M., Nakabeppu Y., Yamagata Y.
  • Journal Title: Acta Crystallograph.Sect.F.Struct.Biol.Cryst.Commun. 62・12 Pages: 1283-1285
• [Journal Article] The human <HYMAI/PLAGL1> differentially methylated region acts as an imprint control region in mice. (2006)
  • Author(s): Arima T., Yamasaki K., John R.M., Kato K., Sakumi K., Nakabeppu Y., Wake N., Kono T.
  • Journal Title: Genomics 88・5 Pages: 650-658
• [Journal Article] Galectin-1 is essential in fumor angiogenesis and is a target for antiangiogenesis therapy. (2006)
  • Author(s): Thijssen V.L., Postel R., Brandwijk R.J., Dings R.P., Nesmelova I., Satijn S., Verhofstad N., Nakabeppu Y., Baum L.G., Bakkers J., Mayo K.H., Poirier F., Griffioen A.W.
  • Journal Title: Proc.Natl.Acad.Sci.U.S.A. 103・43 Pages: 15975-15980
• [Journal Article] Contrasting genome-wide distribution of 8-hydroxyguanine and acrolein-modified adenine during oxidative stress-induced renal carcinogenesis. (2006)
  • Author(s): Akatsuka S., Aung T.T., Dutta K.K., Jiang L., Lee W.H., Liu Y.T., Onuki J., Shirase T., Yamasaki K., Ochi H., Naito Y., Yoshikawa T., Kasai H., Tominaga Y., Sakumi K., Nakabeppu Y., Kawai Y., Uchida K., Yamasaki A., Tsuruyama T., Yamada Y., Toyokuni S.
  • Journal Title: Am.J.Pathol. 169・4 Pages: 1328-1342
• [Journal Article] Up-regulation of hMUTYH, a DNA repair enzyme, in the mitochondria of substantia nigra in Parkinson's disease. (2006)
  • Author(s): Arai T., Fukae J., Hatano T., Kubo S., Ohtsubo T., Nakabeppu Y., Mori H., Mizuno Y., Hattori N.
  • Journal Title: Acta Neuropathol. 112・2 Pages: 139-145
• [Journal Article] The GT to GC single nucleotide polymorphism at the beginning of an altemative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal. (2006)
  • Author(s): Sakai Y., Oda H., Yoshimura D., Furuichi M., Kang D., Iwai S., Hara T., Nakabeppu Y.
  • Journal Title: J.Mol.Med. 84・8 Pages: 660-670
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides. (2006)
  • Author(s): Nakabeppu Y., Kajitani K., Sakamoto K., Yamaguchi H., Tsuchimoto D.
  • Journal Title: DNA Repair 5・7 Pages: 761-772
• [Journal Article] Angiotensin I-converting enzyme gene polymorphism modifies the smoking-cancer association : the Hisayama Study. (2006)
  • Author(s): Arima H., Kiyohara Y., Tanizaki Y., Nakabeppu Y., Kubo M., Kato I., Sueishi K., Tsuneyoshi M., Fujishima M., Iida M.
  • Journal Title: Eur.J.Cancer Prev. 15・3 Pages: 196-201
• [Journal Article] A genome-wide distribution of 8-oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome. (2006)
  • Author(s): Ohno M., Miura T., Furuichi M., Tominaga Y., Tsuchimoto D., Sakumi K., Nakabeppu Y.
  • Journal Title: Genome Res. 16・5 Pages: 567-575
• [Journal Article] Neonatal Ventral Hippocampal Lesions Produce an Elevation of ΔFosB-like Protein(s) In the Rodent Neocortex. (2006)
  • Author(s): Powell K., Binder T.L., Hori S., Nakabeppu Y.R.D, Weinberger Lipska B.K., Robertson G.S.
  • Journal Title: Neuropsychopharmacology 31・4 Pages: 700-711
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. (2006)
  • Author(s): Yamaguchi H., Kajitani K., Dan Y., Furuichi M., Ohno M., Sakumi K., Kang D., Nakabeppu Y.
  • Journal Title: Cell Death Differ. 13・4 Pages: 551-563
• [Journal Article] Mutagenesis and carcinogenesis caused by the oxidation of nucleic acids. (2006)
  • Author(s): Nakabeppu Y., Sakumi K., Sakamoto K., Tsuchimoto D., Tsuzuki T., Nakatsu Y.
  • Journal Title: Biol.Chem. 387・4 Pages: 373-379
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, suppresses the accumulation of oxidative damage of nucleic acids in the hippocampal microglia during kanate-induced excitotoxicity. (2006)
  • Author(s): K.Kajitani et al.
  • Journal Title: Journal of Neuroscience 26(6) Pages: 1688-1698
• [Journal Article] Mutagenesis and Carcinogenesis Caused by the Oxidation of Nucleic Acids. (2006)
  • Author(s): Y.Nakabeppu, et al.
  • Journal Title: Biological Chemistry 387(in press)
• [Journal Article] Prevention of the mutagenecity and cytotoxicity of oxidized purine nucleotides. (2006)
  • Author(s): Y.Nakabeppu et al.
  • Journal Title: Oxidative Damage to Nucleic Acids On line
• [Journal Article] The GT to GC single nucleotide polymorphism at the beginning of an alternative exon 2C of human MTH1 gene confers an amino terminal extension that functions as a mitochondrial targeting signal. (2006)
  • Author(s): Y.Sakai et al.
  • Journal Title: Journal of Molecular Medicine (in press)
• [Journal Article] Novel Role of Neuronal Ca^<2+> Sensor-1 as a Survival Factor Up-Regulated in Injured Neurons. (2006)
  • Author(s): T.Y.Nakamura et al.
  • Journal Title: Journal of Cell Biology (in press)
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides (2006)
  • Author(s): Y.Nakabeppu et al.
  • Journal Title: DNA Repair (in press)
• [Journal Article] Regulation of the Neuronal Fate by ΔFosB and its Downstream Target, Galectin-1. (2005)
  • Author(s): T.Miura, et al.
  • Journal Title: Current Drug & Targets 6(4) Pages: 437-444
• [Journal Article] Selective induction of ΔFosB in the brain after transient forebrain ischemia accompanied by an increased expression of galectin-1, and the implication of ΔFosB and galectin-1 in neuroprotection and neurogenesis. (2005)
  • Author(s): H.Kurushima et al.
  • Journal Title: Cell Death & Differentiation 12(8) Pages: 1078-1096
• [Journal Article] Neonatal Ventral Hippocampal Lesions Produce an Elevation of ΔFosB-like Protein(s) In the Rodent Neocortex. (2005)
  • Author(s): K.J.Powell et al.
  • Journal Title: Neuropsychopharmacology On line
• [Journal Article] MTH1, an oxidized purine nucleoside triphosphatase, protects the dopamine neurons from oxidative damage in nucleic acids caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. (2005)
  • Author(s): H.Yamaguchi et al.
  • Journal Title: Cell Death & Differentiation On line
• [Presentation] Oxidative damage in nucleic acids in Huntington's disease model (2007)
  • Author(s): Sheng Z, et. al.
  • Organizer: 第30回日本神経科学大会・第50回日本神経化学会大会・第17回日本神経回路学会大会 合同学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-09-10
• [Presentation] Cell death caused by 8-oxoguanine (2007)
  • Author(s): Nakabeppu Y
  • Organizer: 3rd Japan-US DNA Repair Meeting
  • Place of Presentation: Akiu,Sendai,
  • Year and Date: 2007-05-08
• [Book] Prevention of the mutagenecity and cytotoxicity of oxidized purine nucleotides. In Evans, M.D. and Cooke, M.S.(eds), Oxidative Damage to Nucleic Acids. (2007)
  • Author(s): Nakabeppu Y, et. al.
  • Publisher: Springer, Austin, TX
• [Book] Prevention of the mutagenecity and cytotoxicity of oxidized purine nucleotides, Oxidative Damage to Nucleic Acids (2007)
  • Author(s): Nakabeppu Y., Behmanesh M., Yamaguchi H., Yoshimura D., Sakumi K.
  • Total Pages: 14
  • Publisher: Landes Bioscience/Eurekah, Georgetown, TX. USA
• [Book] DNA Replication and Transcription(Meyers RA, editor). Genomics and Genetics : From Molecular Details to Analysis and Techniques. (2007)
  • Author(s): Nakabeppu Y, Maki H, Sekiguchi M
  • Total Pages: 27
  • Publisher: Wiley-VCH Verlag GmbH ＆ Co., Weinheim, Germany