Functional analysis of DJ-1, a causative gene for familial Parkinson's disease, and its pharmaceutical application

• Project/Area Number: 21390014
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Hokkaido University
• Principal Investigator: ARIGA Hiroyoshi 北海道大学, 大学院・薬学研究院, 教授 (20143505)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2011: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2010: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2009: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 脳神経疾患 / 癌 / ストレス / 蛋白質 / 遺伝子 / DJ-1 / パーキンソン病 / ドパミン / ミトコンドリア / 複合体I / チロシン水酸化酵素 / DJ-1結合化合物 / 創薬

Research Abstract

We found that DJ-1 positively regulates synthesis and secretion of dopamine through direct interaction of DJ-1 with tyrosine hydroxylase, L-DOPA decarboxylase and VMAT-2 and through upregulation of their gene expression and that DJ-1 also positively regulates enzymatic activity of mitochondrial complex I. Furthermore, we isolated DJ-1-binding compounds that restored locomotion defect and inhibited neuronal cell death in Parkinson's disease and stroke model animals.

Research Products

• [Journal Article] Stimulation of vesicular monoamine transporter 2 activity by DJ-1 in SH-SY5Y cells (2012)
  • Author(s): Ishikawa, S., Tanaka, Y., Takahashi-Niki, K., Niki, T., Ariga, H., Iguchi-Ariga, S. M. M.
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 42 Issue: 4 Pages: 813-818
  • DOI: 10.1016/j.bbrc.2012.04.095
  • Peer Reviewed
• [Journal Article] Transcriptional activation of low-density lipoprotein 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., Ariga, H.
  • Journal Title: PLoS ONE Volume: 7 Issue: 5 Pages: e38144-e38144
  • DOI: 10.1371/journal.pone.0038144
  • Peer Reviewed
• [Journal Article] CHFR regulates the mitotic checkpoint by targeting PARP-1 for ubiquitination and degradation (2012)
  • Author(s): Kashima, L., Idogawa, M., Mita, H., Shitashige, M., Yamada, T., Ogi, K., Suzuki, H., Toyota, M., Ariga, H., Sasaki, Y., Tokino, T.
  • Journal Title: J. Biol. Chem Volume: 287 Issue: 16 Pages: 12975-12984
  • DOI: 10.1074/jbc.m111.321828
  • 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., Ariga, H.
  • Journal Title: J. Pharmacol. Sci Volume: 115 Pages: 36-44
  • Peer Reviewed
• [Journal Article] A novel signaling pathway mediated by the nuclear targeting of C-terminal fragments of mammalian Patched 1 (2011)
  • Author(s): Kagawa, H., Shino, Y., Kobayashi, D., Demizu, S., Shimada, M., Ariga, H., Kawahara, H.
  • Journal Title: PLoS ONE Volume: 6 Issue: 51 Pages: 39718-39731
  • DOI: 10.1074/jbc.m110.137034
  • Peer Reviewed
• [Journal Article] Identification and characterization of an oocyte factor required for development of porcine nuclear transfer embryos (2011)
  • Author(s): Miyamoto, K., Nagai, K., Kitamura, N., Nishikawa, T., Ikegami, H., Binh, N., Tsukamoto, S., Matsumoto, M., Tsukiyama, T., Minami, N., Yamada, M., Ariga, H., Miyake, M., Kawarasaki, T., Matsumoto, K., Imai, H.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 108 Issue: 17 Pages: 7040-7045
  • DOI: 10.1073/pnas.1013634108
  • Peer Reviewed
• [Journal Article] Prefoldin subunits are protected from ubiquitin-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., Ariga, H.
  • Journal Title: J. Biol. Chem Volume: 286 Issue: 22 Pages: 1919-19203
  • DOI: 10.1074/jbc.m110.216259
  • Peer Reviewed
• [Journal Article] DJ-1 associates with synaptic membranes (2011)
  • Author(s): Yukiko Usami, Taku Hatano, Satoshi Imai, Shin-ichiro Kubo, Shigeto Sato, Shinji Saiki, Yoichiro Fujioka, Yusuke Ohba, Fumiaki Sato, Manabu Funayama. Hiroto Eguchi, Kaori Shiba, Hiroyoshi Ariga, Jie Shen, Nobutaka Hattori
  • Journal Title: Neurobiology of Disease Volume: 43 Issue: 3 Pages: 651-662
  • DOI: 10.1016/j.nbd.2011.05.014
  • 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., Ariga, H.
  • Journal Title: Mol. Neurodegeneration Volume: 6 Issue: 1 Pages: 48-48
  • DOI: 10.1186/1750-1326-6-48
  • Peer Reviewed
• [Journal Article] Protection Against Dopaminergic Neurodegeneration in Parkinson's Disease-Model Animals by a Modulator of the Oxidized Form of DJ-1, a Wild-type of Familial Parkinson's Disease-Linked PARK7 (2011)
  • Author(s): Inden, M., Kitamura, M., Takahashi, K., Takata, K., Ito, N., Niwa, R., Funayama, R., Nishimura, K., Taniguchi, T., Honda, T., Taira, T., Ariga, H.
  • Journal Title: Journal of Pharmacological Sciences Volume: 117 Issue: 3 Pages: 189-203
  • DOI: 10.1254/jphs.11151FP
  • NAID: 10030453398
  • ISSN: 1347-8613, 1347-8648
  • 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.
  • Journal Title: J.Pharmacol.Sci Volume: 115 Pages: 36-44
  • 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., Ariga, H.
  • Journal Title: FEBS Lett Volume: 584 Issue: 18 Pages: 3891-3895
  • DOI: 10.1016/j.febslet.2010.08.010
  • Peer Reviewed
• [Journal Article] Human DJ-1-specific transcriptional activation of tyrosine hydroxylase gene (2010)
  • Author(s): Ishikawa, S.
  • 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.
  • Journal Title: FEBS Lett. Volume: 584 Pages: 3891-3895
  • Peer Reviewed
• [Journal Article] PAPA-1 is a nuclear binding partner of IGFBP-2 and modulates its growth promoting actions (2009)
  • Author(s): Miyako, K., Cobb, L. J., Francis, M., Huang, A., Peng, B., Pintar, J. E., Ariga, H., Cohen, P.
  • Journal Title: Mol. Endocrinol Volume: 23 Issue: 2 Pages: 169-175
  • DOI: 10.1210/me.2008-0168
  • Peer Reviewed
• [Journal Article] Protection Against Oxidative Stress-Induced Neurodegeneration by a Modulator for DJ-1, the Wild-Type of Familial Parkinson's Disease-Linked PARK7 (2009)
  • Author(s): Yanagida, T., Kitamura, Y., Yamane, K., Takahashi, K., Takata, K., Yanagisawa, D., Yasui, H., Taniguchi, T., Taira, T., Honda, T., Ariga, H.
  • Journal Title: Journal of Pharmacological Sciences Volume: 109 Issue: 3 Pages: 463-468
  • DOI: 10.1254/jphs.08323SC
  • NAID: 130000106980
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Oxidative stress induction of DJ-1 protein in reactive astrocytes scavenges free radicals and reduces cell injury. Oxid. Med (2009)
  • Author(s): Yanagida, T., Tsushima, J., Kitamura, Y., Yanagisawa, D., Takata, K., Shibaike, T., Yamamoto, A., Taniguchi, T., Yasui, H., Taira, T., Morikawa, S., Inubushi, T., Tooyama, I., Ariga, H.
  • Journal Title: Cell. Long Volume: 1 Pages: 36-42
  • URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763229/?tool=pubmed
  • Peer Reviewed
• [Journal Article] Kaempferol Derivatives Prevent Oxidative Stress-Induced Cell Death in a DJ-1-Dependent Manner (2009)
  • Author(s): Qu, W., Fan, L., Kim, Y.-C., Ishikawa, S., Iguchi-Ariga, S. M. M., Pu, X.-P., Ariga, H.
  • Journal Title: Journal of Pharmacological Sciences Volume: 110 Issue: 2 Pages: 191-200
  • DOI: 10.1254/jphs.09045FP
  • NAID: 10025737178
  • ISSN: 1347-8613, 1347-8648
• [Journal Article] Neuroprotective effect of the antiparkinsonian drug pramipexole against nigrostriatal dopaminergic degeneration in rotenone-treated mice (2009)
  • Author(s): Inden, M., Kitamura, Y., Tamaki, A., Yanagida, T., Shibaike, T., Yamamoto, A., Takata, K., Yasui, H., Taira, T., Ariga, H., Taniguchi, T.
  • Journal Title: Neurochem. Int Volume: 55 Issue: 8 Pages: 760-767
  • DOI: 10.1016/j.neuint.2009.07.009
  • Peer Reviewed
• [Journal Article] Oxidation of DJ-1-dependent cell transformation through direct binding of DJ-1 to PTEN. Int (2009)
  • Author(s): Kim, Y.-C., Kitaura, H., Taira, T., Iguchi-Ariga, S. M. M., Ariga, H.
  • Journal Title: J. Oncol Volume: 35 Issue: 06 Pages: 1331-1341
  • DOI: 10.3892/ijo_00000451
  • Peer Reviewed
• [Journal Article] Oxidative status of DJ-1-dependent activation of dopamine synthesis through interaction of tyrosine hydroxylase and 4-dihydroxy-l-phenylalanine (l-DOPA) decarboxylase with DJ-1 (2009)
  • Author(s): Ishikawa, S., Taira, T., Niki, T., Takahashi-Niki, K., Maita, C., Maita, H., Ariga, H., Iguchi-Ariga, S. M. M.
  • Journal Title: J. Biol. Chem Volume: 284 Issue: 42 Pages: 28832-28844
  • DOI: 10.1074/jbc.m109.019950
  • Peer Reviewed
• [Journal Article] Recombinant human DJ-1 protein has a protective effect for dopaminergic neurons (2009)
  • Author(s): Kitamura, Y., Yanagida, T., Takata, K., Taniguchi, T., Ariga, H.
  • Journal Title: Current Topics in Peptide & Protein Research Volume: 9 Pages: 47-55
  • Peer Reviewed
• [Journal Article] DJ-1 binds to mitochondrial complex I and maintains its activity (2009)
  • Author(s): Hayashi, T., Ishimori, C., Takahashi-Niki, K., Taira, T., Kim, Y-C., Maita, H., Maita, C., Ariga, H.,
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 390 Pages: 667-672
  • Peer Reviewed
• [Journal Article] Oxidative neurodegeneration is prevented by UCP0045037, an allosteric modulator for the reduced form of DJ-1, a wild-type of familial Parkinson's dsease-lnked PARK7. Int (2009)
  • Author(s): Yamane, K., Kitamura, Y., Yanagida, T., Takata, T., Yanagisawa, D., Taniguchi, T., Taira, T., Ariga, H.
  • Journal Title: J. Mol. Sci Volume: 10 Issue: 11 Pages: 4789-4804
  • DOI: 10.3390/ijms10114789
  • Peer Reviewed
• [Journal Article] Oxidative status of DJ-1-dependent activation of dopamine synthesis through interaction of tyrosine hydroxylase and 4-dihydroxy-1-phenylalanine(1-DOPA)decarboxylase with DJ-1 (2009)
  • Author(s): Ishikawa, S.
  • Journal Title: J.Biol.Chem. 284 Pages: 28832-28844
  • Peer Reviewed
• [Journal Article] DJ-1 binds to mitochondrial complex I and maintains its activity (2009)
  • Author(s): Hayashi, T.
  • Journal Title: Biochem.Biophys.Res.Commun. 390 Pages: 667-672
  • Peer Reviewed
• [Journal Article] Oxidative stress induction of DJ-1 protein in reactive astrocytes scavenges free radicals and reduces cell injury. (2009)
  • Author(s): Yanagida, T.
  • Journal Title: Oxid.Med.Cell.Long. 1 Pages: 36-42
  • Peer Reviewed
• [Presentation] バーチャルスクリーニングによるパーキンソン病治療薬の開発 (2011)
  • Author(s): 有賀寛芳
  • Organizer: 第91回日本化学会春秀年会シンポジウム
  • Place of Presentation: 横浜 招待講演
  • Year and Date: 2011-03-26
• [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: 長崎大学(長崎市)
• [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., Ariga, H.
  • Organizer: ISN-ESN 201123rd Biennial Meeting
  • Place of Presentation: Athens Convention Center (Greece)
• [Presentation] Role of DJ-1 as an anti-oxidative stress sensor (2011)
  • Author(s): Niki, K, Niki, T., Iguchi-Ariga, S. M. M., Ariga, H.
  • Organizer: ISN-ESN 201123rd Biennial Meeting
  • Place of Presentation: Athens Convention Center (Greece)
• [Presentation] DJ-1 oxidized at C106 inhibits p53-activated DUSP1 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., Ariga, H.
  • Organizer: The 41th annual meeting of the Society for Neuroscience
  • Place of Presentation: Washington Convention Center (USA)
• [Presentation] Prefoldin protects neuronal cells from polyglutamine toxicity by preventing aggregation at small oligomer state (2011)
  • Author(s): Tashiro, E, Muto, H., Zako, T., Miyazawa, M., Kitaura, H., Kitamura, A., Kubota, H., Kinjo, M., Ariga, H.
  • Organizer: The 41th annual meeting of the Society for Neuroscience
  • Place of Presentation: Washington Convention Center (USA)
• [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: Washington Convention Center (USA)
• [Presentation] DJ-1のミトコンドリアにおける機能 (2011)
  • Author(s): 仁木(高橋)加寿子、仁木剛史、米田千夏、我那覇洋子、有賀(井口)早苗、有賀寛芳
  • Organizer: 日本薬学会第132年会シンポジウム
  • Place of Presentation: 北海道大学(札幌市)
• [Presentation] バーチャルスクリーニングによるパーキンソン病治療薬の開発 (2011)
  • Author(s): 有賀寛芳
  • Organizer: 第91回日本化学会シンポジウム
  • Place of Presentation: 神奈川大学(横浜市)
• [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., Iguchi-Ariga, S. M. M.
  • Organizer: The 40th annual meeting of the Society for Neuroscience
  • Place of Presentation: San Diego Convention Center (USA)
• [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
  • Place of Presentation: San Diego Convention Center (USA)
• [Presentation] Function of DJ-1 and its therapeutic application to Parkinson's disease (2009)
  • Author(s): Hiroyoshi Ariga
  • Organizer: The 22nd Biennial Joint Meeting of the International Society for Neurochemistry(ISN)and the Asian Pacific Society for Neurochemistry(APSN)
  • Place of Presentation: Busan, Korea
  • Year and Date: 2009-08-28
• [Presentation] 大学化合物ライブラリーを用いたパーキンソン病治療薬のin siloco開発 (2009)
  • Author(s): 有賀寛芳
  • Organizer: 第293回CBI学会
  • Place of Presentation: 東京大学(東京都文京区)
  • Year and Date: 2009-01-16
• [Presentation] Oxidation of DJ-1-dependent regulation of tyrosine hydroxylase (2009)
  • Author(s): Ishikawa, S., Taira, T., Niki, T., Takahashi, K., Ariga, H., Iguchi-Ariga, S. M. M.
  • Organizer: The 39th annual meeting of the Society for Neuroscience
  • Place of Presentation: Chicago Convention Center (USA)
• [Presentation] Effects of MM-1 and molecular chaperones on formation of polyglutamine aggregation (2009)
  • Author(s): Tashiro, E., Miyazawa, M., Kitaura, H., M., Iguchi-Ariga, S. M. M., Ariga, H.
  • Organizer: The 39th annual meeting of the Society for Neuroscience
  • Place of Presentation: Chicago Convention Center (USA)
• [Presentation] Function of DJ-1 and its therapeutic application to Parkinson's disease (2009)
  • Author(s): Ariga, H., Kitamura, Y., Iguchi-Ariga, S. M. M.
  • Organizer: 22rd Annual meeting for International Society for Neurochemistry
  • Place of Presentation: Busan Exhibition Convention Center (Korea)
• [Presentation] Oxidative status of DJ-1-dependent regulation of the p53 signaling (2009)
  • Author(s): Kato, I., Maita, H., Iguchi-Ariga, S. M. M., Ariga, H.
  • Organizer: 22rd Annual meeting for International Society for Neurochemistry
  • Place of Presentation: Busan Exhibition Convention Center (Korea)
• [Presentation] Inhibition of PTEN phosphatase activity by the direct interaction of DJ-1 with PTEN under the oxidative conditions (2009)
  • Author(s): Kim, Y-C., Kitaura, H., Taira, T., Iguchi-Ariga, S. M. M., Ariga, H.
  • Organizer: 22rd Annual meeting for International Society for Neurochemistry
  • Place of Presentation: Busan Exhibition Convention Center (Korea)
• [Book] 酸化ストレス防御系の破綻とパーキンソン病、別冊・医学のあゆみ「ここまでわかったミトコンドリア研究の新展開」 (2011)
  • Author(s): 有賀寛芳、有賀早苗
  • Publisher: 医歯薬出版
• [Book] 別冊・医学のあゆみ「ここまでわかったミトコンドリア研究の新展開」 (2011)
  • Author(s): 有賀寛芳
  • Publisher: 医歯薬出版
• [Book] ここまでわかったミトコンドリア研究の新展開 (2011)
  • Author(s): 有賀寛芳(共著)
  • Publisher: 医歯薬出版
• [Book] 別冊・医学のあゆみ「ここまでわかったパーキンソン病研究」抗酸化ストレス因子としてのPark7/DJ-1とパーキンソン病 (2009)
  • Author(s): 有賀寛芳、有賀早苗
  • Publisher: 医歯薬出版
• [Book] ここまでわかったパーキンソン病研究-抗酸化ストレス因子としてのPark7/DJ-1とパーキンソン病 (2009)
  • Author(s): 有賀寛芳、有賀早苗
  • Total Pages: 5
  • Publisher: 医歯薬出版
• [Remarks]
  • URL: http://bunseiserver.pharm.hokudai.ac.jp/
• [Patent(Industrial Property Rights)] 神経変性疾患治療薬 (2011)
  • Inventor(s): 有賀寛芳
  • Industrial Property Rights Holder: 有賀寛芳
  • Filing Date: 2011-03-25
  • Overseas
• [Patent(Industrial Property Rights)] 神経変性疾患治療薬 (2011)
  • Inventor(s): 有賀寛芳
  • Industrial Property Rights Holder: 北海道大学
  • Filing Date: 2011-03-25
  • Overseas
• [Patent(Industrial Property Rights)] パーキンソン病治療薬としての生薬由来化合物 (2010)
  • Inventor(s): 蒲小平、有賀寛芳、高建偉
  • Industrial Property Rights Holder: 蒲小平、有賀寛芳、高建偉
  • Filing Date: 2010-10-28
  • Overseas
• [Patent(Industrial Property Rights)] 神経変性疾患治療薬 (2010)
  • Inventor(s): 有賀寛芳
  • Industrial Property Rights Holder: 有賀寛芳
  • Industrial Property Number: 2010-072820
  • Filing Date: 2010-03-26