Pathogenic mechanisms of Parkinson's disease via DJ-1 and targeted drug development

2012 Fiscal Year Final Research Report

• Project/Area Number: 22300119
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Hokkaido University
• Principal Investigator: ARIGA Sanae 北海道大学, 大学院・農学研究院, 教授 (90184283)
• Project Period (FY): 2010 – 2012
• Keywords: 脳神経変性疾患 / 癌 / ストレス / 蛋白質 / 遺伝子

Research Abstract

Molecular mechanisms of Parkinson’s disease pathogenesis were analyzed by functional analyses of DJ-1 protein, the product of protooncogene DJ-1, also identified as PARK7, a responsible gene for familial Parkinson’s disease. We revealed that DJ-1 transactivated key enzymes for dopamine biosynthesis, specifically bound to a dopamine transporter VMAT-2, transactivation of Nrf2-dependent anti-oxidative stress genes via specific binding and inhibition of PTEN, and was required for neurite formation in cooperation with Drebrin, an actin-binding protein. As for drug development, several low-molecular chemicals specifically bound to DJ-1 prohibited hyperoxidation of the protein and preserved a variety of physiological activities of DJ-1 under oxidative stress conditions. The chemicals were thus suggested to be promising candidates for preventive and curative drug for Parkinson’s disease.

Research Products

• [Journal Article] Monomer DJ-1 and its N-terminal sequence are necessary for mitochondrial localization of DJ-1 mutants (2013)
  • Author(s): Maita, C., Maita, H., Iguchi-Ariga, S.M.M. and Ariga, H
  • Journal Title: PLoS ONE Volume: 8(1) Pages: e54087
  • Peer Reviewed
• [Journal Article] Oxidized DJ-1 inhibits p53 by sequestering p53 from promoters in a DNA-binding affinity-dependent manner (2013)
  • Author(s): Kato, I., Maita, H., Takahashi-Niki, K., Saito, Y., Noguchi, N., Iguchi-Ariga, S.M.M. and Ariga, H
  • Journal Title: Mol. Cell. Biol Volume: 33(2) Pages: 340-359
  • Peer Reviewed
• [Journal Article] Rabring7 degrades c-Myc through complex formation with MM-1 (2012)
  • Author(s): Narita, R., Kitaura, H., Torii, A., Tashiro, E., Miyazawa, M., Ariga, H., and Iguchi-Ariga, S.M.M
  • Journal Title: PLoS ONE PLoS ONE Volume: 7(7) Pages: e41891
  • Peer Reviewed
• [Journal Article] Transcriptional activation of low-densitylipoprotein receptor gene by DJ-1 and effect of DJ-1 on cholesterol homeostasis (2012)
  • Author(s): Yamaguchi, S., Yamane, T., Takahashi-Niki, K., Kato, I., Niki, T., Goldberg, M.S., Shen, J., Ishimoto, K., Doi, T., Iguchi-Ariga, S.M.M. and Ariga, H
  • Journal Title: PLoS ONE Volume: 7(5) Pages: e38144
  • Peer Reviewed
• [Journal Article] Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells.Biochem (2012)
  • Author(s): Ishikawa, S., Tanaka, Y., Takahashi-Niki, K., Niki, T., Ariga, H. and Iguchi-Ariga, S.M.M
  • Journal Title: Biophys. Res. Commun Volume: 42(4) Pages: 813-818
  • Peer Reviewed
• [Journal Article] Neuroprotective effect of a new DJ-1-binding compound against neurodegeneration in Parkinson's disease and stroke model rats (2011)
  • Author(s): Kitamura, Y., Watanabe, S., Taguchi, M., Takagi, K., Kawata, T., Takahashi-Niki, K., Yasui, H., Maita, H., Iguchi-Ariga, S.M.M. and Ariga, H
  • Journal Title: Mol. Neurodegeneration Volume: 6 (1) Pages: 48-66
  • Peer Reviewed
• [Journal Article] Prefoldin subunits are protected fromubiquitin-proteasome system-mediated degradation by forming complex with other constituent subunits (2011)
  • Author(s): Miyazawa, M., Tashiro, E., Kitaura, H., Maita, H., Suto, H., Iguchi-Ariga, S.M.M. and Ariga, H
  • Journal Title: J. Biol. Chem Volume: 286 (22) Pages: 19191-19203
  • Peer Reviewed
• [Journal Article] DJ-1-mediated Protective Effect of Protocatechuic Aldehyde against Oxidative Stress in SH-SY5Y cells (2011)
  • Author(s): Gao, J-W., Yamane, T., Maita, H., Ishikawa, S., Iguchi-Ariga, S.M.M., Pu, X-P. and Ariga, H
  • Journal Title: J. Pharmacol. Sci Volume: 115(1) Pages: 36-44
  • Peer Reviewed
• [Journal Article] Human DJ-1-specific transcriptional activation of tyrosine hydroxylase gene (2010)
  • Author(s): Ishikawa, S., Taira, T., Takahashi-Niki, K., Niki, T., Ariga, H. and Iguchi-Ariga, S.M.M
  • Journal Title: J. Biol. Chem Volume: 285 Pages: 39718-39731
  • Peer Reviewed
• [Journal Article] DJ-1, an oncogene and causative gene for familial Parkinson's disease,is essential for SV40 transformation in mouse fibroblasts through up-regulation of c-Myc (2010)
  • Author(s): Kim Y.C., Kitaura, H., Iguchi-Ariga, S.M.M. and Ariga, H
  • Journal Title: FEBS Lett Volume: 584 Pages: 3891-3895
  • Peer Reviewed
• [Journal Article] Report on the Women in PhysiologySymposium in IUPS 2009 (2010)
  • Author(s): Kimura, J., Suzuki, Y., Mizumura, K., Katagiri, C., Azuma, K., Hao, L.Y., Gulia, K.K., Wray, S., Iguchi-Ariga, S.M.M. and Barrett, K.E
  • Journal Title: J. Physiol. Sci Volume: 60 Pages: 227-234
  • Peer Reviewed
• [Presentation] Function of DJ-1 and its therapeutic application to Parkinson's disease (2012)
  • Author(s): Ariga, H., Kitamura, Y. & Iguchi-Ariga, S.M.M.
  • Organizer: The BRC International Conference
  • Place of Presentation: ShineVilleResort, Jeju Island, Korea
  • Year and Date: 20120627-29
• [Presentation] DJ-1 とプロリン生合成酵素 PYCR1 の相互作用の解析 (2012)
  • Author(s): 安田樹、梶勇輔、我妻智博、仁木剛史、有 賀寛芳、 有賀(井口)早苗
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-12-16
• [Presentation] パーキンソン 病原因遺伝子産物 DJ-1 による酸化ストレス 依存的な p53 機能調節機構の解析 (2012)
  • Author(s): 加藤いづみ、米田宏、仁木(高橋)加寿子、 有 賀(井口)早苗 、有賀寛芳
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-12-16
• [Presentation] パーキンソン病原因遺伝子産物 DJ-1 とその結合化合物による酸化ストレス誘導 Nrf2 転写活性化能に対する影響 (2012)
  • Author(s): 仁木剛史、仁木(高橋)加寿子、岡本麻美、 遠藤仁郎、有賀寛芳、有賀(井口)早苗
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-12-15
• [Presentation] DJ-1 の PTEN、Nrf2 を介 した細胞死抑制に対する DJ-1 結合化合物の効果 (2012)
  • Author(s): 遠藤仁郎、仁木剛史、岡本麻美、有賀寛芳、 有 賀(井 口)早苗
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-12-15
• [Presentation] DJ-1 とプロリン 生合成酵素 PYCR1 の相互作用の解析 (2012)
  • Author(s): 安田樹、梶勇輔、我妻智博、仁木剛史、有 賀寛芳、 有賀(井口) 早苗
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-12-15
• [Presentation] パーキンソン病原因遺伝子産物 DJ-1 とスパイン形成制御因子 Drebrin の相互作用の解析 (2012)
  • Author(s): 近藤珠代、石川静麻、仁木(高橋)加寿子、 仁木剛史、有賀寛芳、有賀(井口)早苗
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2012-12-14
• [Presentation] DJ-1, a familial Parkinson's disease-linked protein, promotes the effect of Drebrin on neurite-like projection formation (2012)
  • Author(s): Kondo, T., Ishikawa, S., Niki, K., Niki, T., Ariga, H.Ariga, H. & Iguchi-Ariga, S.M.M.
  • Organizer: The 11th Biennial Meeting of the Asian-Pacific Society for Neurochemistry / 55th Annual Meeting of the Japanese Society for Neurochemistry
  • Place of Presentation: Kobe International Conference Center, Japan
  • Year and Date: 2012-09-30
• [Presentation] Analysis of interaction between DJ-1 and PYCR1 (2012)
  • Author(s): Yasuda, T., Kaji, Y. Agatsuma, T., Niki, T., Ariga, H.Ariga, H. & Iguchi-Ariga, S.M.M.
  • Organizer: The 11th Biennial Meeting of the Asian-Pacific Society for Neurochemistry / 55th Annual Meeting of the Japanese Society for Neurochemistry
  • Place of Presentation: Kobe International Conference Center, Japan
  • Year and Date: 2012-09-30
• [Presentation] DJ-1 inhibits affects cell protection under the oxidative stress condition through regulating DNA-binding activity of p53 (2012)
  • Author(s): Kato, I., Maita, H., Takahashi-Niki, K., Iguchi-Ariga, S.M.M. & Ariga, H. Oxidized
  • Organizer: The 11th Biennial Meeting of the Asian-Pacific Society for Neurochemistry/ 55th Annual Meeting of the JapaneseSociety for Neurochemistry
  • Place of Presentation: Kobe International ConferenceCenter, Japan
  • Year and Date: 2012-09-30
• [Presentation] Oxidative stress-response by DJ-1 and its binding compounds (2012)
  • Author(s): Niki, T., Niki-Takahashi, K., Okamoto, A., Endo, J., Miyakawa, T., Ariga, H. & Iguchi-Ariga, S.M.M.
  • Organizer: The 11th Biennial Meeting of the Asian-Pacific Society for Neurochemistry / 55th Annual Meeting of the Japanese Society for Neurochemistry
  • Place of Presentation: Kobe International Conference Center, Japan
  • Year and Date: 2012-09-30
• [Presentation] パーキンソン病原因遺伝子産物 DJ-1 とスパイン形成制御因子 Drebrin の相互作用の解析 (2012)
  • Author(s): 近藤珠代、石川静麻、仁木(高橋)加寿子、 仁木剛史、有賀寛芳、有賀(井口)早苗
  • Organizer: 第49回日本生化学会北海道支部例会
  • Place of Presentation: 北海道大学札幌キャンパス
  • Year and Date: 2012-07-20
• [Presentation] DJ-1 とプロリン 生合成酵素 PYCR1 の相互作用の解析 (2012)
  • Author(s): 安田樹、梶勇輔、我妻智博、仁木剛史、有賀寛芳、有賀(井口)早苗
  • Organizer: 第49回日本生化学会北海道支部例会
  • Place of Presentation: 北海道大学札幌キャンパス
  • Year and Date: 2012-07-20
• [Presentation] DJ-1 結合化合物による DJ-1 の PTEN 酵素活性抑制機能の調節機構解明 (2012)
  • Author(s): 遠藤仁郎、仁木剛史、岡本麻美、有賀寛芳、有賀(井口)早苗
  • Organizer: 第49回日本生化学会北海道支部例会
  • Place of Presentation: 北海道大学札幌キャンパス
  • Year and Date: 2012-07-20
• [Presentation] DJ-1 と PTEN の相互 作用に対する DJ-1 結合化合物の影響 (2012)
  • Author(s): 遠藤仁郎、仁木剛史、岡本麻美、有賀寛芳、有賀(井口)早苗
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 北海道大学札幌キャンパス
  • Year and Date: 2012-03-30
• [Presentation] DJ-1 とスパイン形成関連タンパク質 Drebrinとの相互作用解析 (2012)
  • Author(s): 近藤珠代、石川静麻、仁木剛史、仁木(高橋) 加寿子、有賀寛芳、有賀(井口)早苗
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 北海道大学札幌キャンパス
  • Year and Date: 2012-03-29
• [Presentation] パーキンソン病原因遺伝子産物 DJ-1 による酸化ストレス依存的な p53 機能調節機構の解析 (2012)
  • Author(s): 加藤いづみ、米田宏、仁木(高橋)加寿子、 有賀(井口)早苗 、有賀寛芳
  • Organizer: 日本薬学会第132年会
  • Place of Presentation: 北海道大学札幌キャンパス
  • Year and Date: 2012-03-29
• [Presentation] DJ-1 とプロリン生合成酵素 PYCR1 との相互作用の解析 (2011)
  • Author(s): 安田樹,梶勇輔,仁木剛史,有賀寛芳, 有賀(井口)早苗
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-12-14
• [Presentation] PAP-1/RP9h による TDG 活性調節機構の解析 (2011)
  • Author(s): 岩澤一史,長岡俊大,楊方偉,米田宏,有賀寛芳,有賀(井口)早苗
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2011-12-14
• [Presentation] DJ-1 oxidized at C106 inhibits p53-activatedDUSP1 expression by sequestering p53 from the promoter through binding to the DNA-binding region of p53 (2011)
  • Author(s): Kato, I., Maita, H., Takahashi-Niki, K, Iguchi-Ariga, S.M.M. and Ariga, H.
  • Organizer: The 41th annual meeting of the Society for Neuroscience
  • Place of Presentation: Walter E. Washington Convention Center, Washington DC, USA
  • Year and Date: 2011-11-14
• [Presentation] Oxidative stress-response by DJ-1 and its binding compounds (2011)
  • Author(s): Niki, T., Takahashi-Niki, K., Okamoto, A., Endo, J., Ariga, H., Iguchi-Ariga, S. M. M.
  • Organizer: The 41th annual meeting of the Society for Neuroscience
  • Place of Presentation: Walter E. Washington Convention Center, Washington DC, USA
  • Year and Date: 2011-11-13
• [Presentation] Function of DJ-1 and its therapeutic application to Parkinson's disease (2011)
  • Author(s): Ariga, H., Kitamura, Y. & Iguchi-Ariga, S.M.M.
  • Organizer: AACL-2011 Japan-Korea Joint conference on brain aging and neurodegeneration
  • Place of Presentation: Nagasaki University, Nagasaki, Japan
  • Year and Date: 2011-10-22
• [Presentation] パーキンソン病原因遺伝子産物 DJ-1 とその結合化合物による酸化ストレ ス誘導 Nrf2 転写活性化能に対する影響 (2011)
  • Author(s): 仁木剛史、仁木(高橋) 加寿子、岡本麻美、遠藤仁朗、瀬在和哉、有賀寛芳、 有賀(井口)早苗
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2011-09-23
• [Presentation] 酸化修飾され たパーキンソン病原因遺伝子産物 DJ-1 は p53 による転写活性化を DNA 結合配列特異的に抑制する (2011)
  • Author(s): 加藤いづみ、米田宏、仁木(高橋)加寿子、有賀(井口)早苗、有賀寛芳
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2011-09-23
• [Presentation] DJ-1 oxidized at C106 inhibits p53-activated DUSP1 expression by sequestering p53 from the promoter (2011)
  • Author(s): Kato, I., Maita, H., Takahashi-Niki, K, Iguchi-Ariga, S.M.M. and Ariga, H.
  • Organizer: ISN-ESN 201123rd Biennial Meeting (International society for neurochemistry with the European society for neurochemistry)
  • Place of Presentation: Megaron Athens International Conference Centre, Athens, Greece
  • Year and Date: 2011-08-30
• [Presentation] Oxidative status of DJ-1 regulates DNA-binding activity of p53. BMB2010 (2010)
  • Author(s): 加藤いづみ、米田宏、 有賀(井口)早苗、 有賀寛芳
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2010-12-08
• [Presentation] パーキンソン病原因遺伝子産物 DJ-1 とその結合化合物による酸化ストレス応答 BMB2010 (2010)
  • Author(s): 仁木剛史、仁木(高橋)加寿子、遠藤仁郎、瀬在和哉、岡本麻美、有賀寛芳、 有賀(井口)早苗
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2010-12-08
• [Presentation] PAP-1 を介したリン酸化シグナルによる TDG 機能調節の可能性 BMB2010 (2010)
  • Author(s): 長岡俊夫、加藤圭祐、楊方偉、米田宏、有賀寛芳、有賀(井口)早苗
  • Organizer: 第33回日本分子生物学会年会・第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2010-12-08
• [Presentation] Human DJ-1-specific transcriptional activation of the tyrosine hydroxylase gene (2010)
  • Author(s): Ishikawa, S., Taira, T., Niki-Takahashi, K., Niki, T., Ariga, H., and Iguchi-Ariga, S.M.M.
  • Organizer: The 40th annual meeting of the Society for Neuroscience
  • Place of Presentation: San Diego Convention Center, San Diego, USA
  • Year and Date: 2010-11-15
• [Presentation] Oxidative status of DJ-1-dependent regulation of the p53 signaling (2010)
  • Author(s): Kato, I., Maita, H., Iguchi-Ariga, S.M.M., Ariga, H.
  • Organizer: The 40th annual meeting of the Society for Neuroscience. The 40th annual meeting of the Society for Neuroscience
  • Place of Presentation: San Diego Convention Center, San Diego, USA
  • Year and Date: 2010-11-15
• [Presentation] Myc-dependent autonomous DNA replication of the sequence upstream of human c-myc gene (2010)
  • Author(s): Okumura, S., Ishikawa, S., Niki, T., Ariga, H., Iguchi-Ariga, S.M.M.
  • Organizer: The 34th FEBS Congress
  • Place of Presentation: Prague Congress Centre, Prague, Czech
  • Year and Date: 2010-09-06
• [Presentation] Human DJ-1-specific transcriptional activation of the tyrosine hydroxylasegene (2010)
  • Author(s): 石川静麻, 平敬宏, 仁木(高橋)加寿子,仁木剛史, 有賀寛芳, 有賀(井口)早苗
  • Organizer: 第33回日本神経科学大会・第53回日本神経化学会大会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 2010-09-03
• [Remarks]
  • URL: http://www.agr.hokudai.ac.jp/emolb/index.html