Detoxification of aldehyde-conjugation as a new mechanism for preventing onset of Parkinson's disease

• Project/Area Number: 18H02443
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: MATSUDA Noriyuki 公益財団法人東京都医学総合研究所, 基礎医科学研究分野, プロジェクトリーダー (10332272)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: DJ-1 / オキソアルデヒド / ヒドロキシ酸 / 解毒 / 加水酵素 / ミトコンドリア / アルデヒド / パーキンソン病 / グリオキサール / メチルグリオキサール / Thermal shift assay / 加水分解酵素

Outline of Final Research Achievements

We have shown that DJ-1, a causative gene product of hereditary recessive Parkinson's disease, has enzymatic activity to hydrolyze α-oxaldehyde (such as glyoxal and methylglyoxal) to α-hydroxy acids. The activity of DJ-1 as α-oxoaldehyde hydratase can be clearly observed in vitro. Moreover, this activity was used as an indicator to identify DJ-1 inhibitors by overseas research groups (e.g., Eur. J. Pharmacol. 2022, Pubmed ID: 35605658), indicating that this enzymatic-activity of DJ-1 is reproducible.
Furthermore, during this research, we found an unexpected link between the "glyoxylate-binding activity of DJ-1 reflecting the α-oxaldehyde hydratase activity" and the "mitochondrial localization of DJ-1 harboring pathogenic mutations".

Academic Significance and Societal Importance of the Research Achievements

多数の論文から、遺伝性潜性パーキンソン病(PD)とミトコンドリアの関連が示唆されている。DJ-1は遺伝性潜性PDの原因因子であり、PD患者由来の変異によってミトコンドリアに移行する。しかしながら、DJ-1の分子機能や病態を導く機序には諸説あり、いまだに混沌としている。
我々は、DJ-1がα-オキソアルデヒドを加水してα-ヒドロキシ酸に変換することを示してきた。さらに研究を進める過程で、DJ-1の酵素活性を反映した「グリオキシル酸との結合」と「DJ-1のミトコンドリア移行」との予期せぬ関連性を見出した。本研究を通じて、DJ-1が遺伝性潜性PDを引き起こす仕組みの理解が進むと期待される。

Research Products

• [Int'l Joint Research] NIH(米国)
• [Int'l Joint Research] NIH/Loyola University Chicago(米国)
• [Journal Article] Mammalian BCAS3 and C16orf70 associate with the phagophore assembly site in response to selective and non-selective autophagy (2021)
  • Author(s): Kojima W, Yamano K, Kosako H, Imai K, Kikuchi R, Tanaka K, Matsuda N
  • Journal Title: Autophagy Volume: - Pages: 2011-2036
  • DOI: 10.1080/15548627.2021.1874133
  • NAID: 120007174412
  • Peer Reviewed / Open Access
• [Journal Article] Cleaved PGAM5 dephosphorylates nuclear serine/arginine-rich proteins during mitophagy. (2021)
  • Author(s): Baba, T., Tanimura, S., Yamaguchi, A., Horikawa, K., Yokozeki, M., Hachiya, S., Iemura, S., Natsume, T., Matsuda, N. and Takeda, K.
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Volume: 11868 Pages: 119045-119045
  • DOI: 10.1016/j.bbamcr.2021.119045
  • Peer Reviewed
• [Journal Article] Loss of peptide: N -glycanase causes proteasome dysfunction mediated by a sugar-recognizing ubiquitin ligase (2021)
  • Author(s): Yoshida Yukiko、Asahina Makoto、Murakami Arisa、Kawawaki Junko、Yoshida Meari、Fujinawa Reiko、Iwai Kazuhiro、Tozawa Ryuichi、Matsuda Noriyuki、Tanaka Keiji、Suzuki Tadashi
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 118
  • DOI: 10.1073/pnas.2102902118
  • Peer Reviewed / Open Access
• [Journal Article] Unfolding is the driving force for mitochondrial import and degradation of the Parkinson's disease-related protein DJ-1 (2021)
  • Author(s): Queliconi BB, Kojima W, Kimura M, Imai K, Udagawa C, Motono C, Hirokawa T, Tashiro S, Caaveiro JMM, Tsumoto K, Yamano K, Tanaka K, Matsuda N
  • Journal Title: J Cell Sci. Volume: 134 Pages: 1-1
  • DOI: 10.1242/jcs.258653
  • Peer Reviewed / Open Access
• [Journal Article] Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL. (2019)
  • Author(s): Koyano, F., Yamano, K., Kosako, H., Tanaka, K., and Matsuda, N.
  • Journal Title: J Biol Chem. Volume: 294 Pages: 10300-10314
  • DOI: 10.1074/jbc.ra118.006302
  • NAID: 120006959752
  • Peer Reviewed / Open Access
• [Journal Article] Parkin-mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes. (2019)
  • Author(s): Koyano, F., Yamano, K., Kosako, H., Kimura, K., Kimura, M., Fujiki, Y., Tanaka, K., and Matsuda, N.
  • Journal Title: EMBO Reports Volume: 20
  • DOI: 10.15252/embr.201947728
  • NAID: 120006942558
  • Peer Reviewed / Open Access
• [Journal Article] PINK1/Parkin 依存性マイトファジーにおける Parkin 活性化の分子機構 (2019)
  • Author(s): 松田憲之
  • Journal Title: 生化学 Volume: 91(5) Pages: 626-633
• [Journal Article] 細胞の恒常性維持を担う動的なユビキチン修飾 (2019)
  • Author(s): 松田憲之
  • Journal Title: 実験医学（増刊号） Volume: 37(7) Pages: 34-46
• [Journal Article] Cleaved PGAM5 is released from mitochondria depending on proteasome-mediated rupture of the outer mitochondrial membrane during mitophagy (2019)
  • Author(s): Yamaguchi Ayane、Ishikawa Hayate、Furuoka Mana、Yokozeki Masashi、Matsuda Noriyuki、Tanimura Susumu、Takeda Kohsuke
  • Journal Title: The Journal of Biochemistry Volume: 165 Pages: 19-25
  • DOI: 10.1093/jb/mvy077
  • NAID: 120006987851
  • Peer Reviewed / Open Access
• [Journal Article] Endosomal Rab cycles regulate Parkin-mediated mitophagy. (2018)
  • Author(s): Yamano, K., Wang, C., Sarraf, S. A., Munch, C., Kikuchi, R., Noda, N. N., Hizukuri, Y., Kanemaki, M. T., Harper, W., Tanaka, K., Matsuda, N., and Youle, R. J.
  • Journal Title: Elife Volume: 7
  • DOI: 10.7554/elife.31326
  • NAID: 120006457172
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structural insights into ubiquitin phosphorylation by PINKI. (2018)
  • Author(s): Okatsu, K., Sato, Y., Yamano, K., Matsuda, N., Negishi, L., Takahashi, A., Yamagata, A., Goto-Ito, S., Mishima, M., Ito, Y., Oka, T., Tanaka, K., and Fukai, S.
  • Journal Title: Sci. Rep. Volume: 8 Pages: 10382-10382
  • DOI: 10.1038/s41598-018-28656-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Discovery and Optimization of Inhibitors of the Parkinson's Disease Associated Protein DJ-1. (2018)
  • Author(s): Tashiro, S. Caaveiro, J. Nakakido, M. Tanabe, A. Nagatoishi, S. Tamura, Y. Matsuda, N. Liu, D.
  • Journal Title: ACS. Chem. Biol. Volume: 13 Pages: 2783-2793
  • DOI: 10.1021/acschembio.8b00701
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] マイトファジー：PINK1とParkinによるミトコンドリア蛋白質の品質管理 (2018)
  • Author(s): 松田憲之、山野晃史
  • Journal Title: 医学のあゆみ Volume: 267(13) Pages: 1056-1062
• [Journal Article] ユビキチンリン酸化 (2018)
  • Author(s): 松田憲之
  • Journal Title: 生体の科学 Volume: 69(5) Pages: 456-457
• [Journal Article] パーキンソン病の病因 2-3-1 “タンパク質・オルガネラ・アルデヒド分解系” (2018)
  • Author(s): 松田憲之
  • Journal Title: 日本臨牀 Volume: 76(4) Pages: 156-161
• [Presentation] 遺伝性パーキンソン病関連タンパク質DJ-1がミトコンドリアに移行する仕組み (2021)
  • Author(s): 松田憲之
  • Organizer: 第20回日本ミトコンドリア学会年会
  • Invited
• [Presentation] DJ-1のアンフォールディングがミトコンドリア移行と分解を引き起こす (2021)
  • Author(s): 松田憲之
  • Organizer: 第44回日本分子生物学会年会
  • Invited
• [Presentation] 損傷ミトコンドリア近傍で Parkin が de novo に隔離膜を形成する分子メカニズム (2021)
  • Author(s): 松田憲之
  • Organizer: 第43回神経組織培養研究会
  • Invited
• [Presentation] 遺伝性パーキンソン病の原因遺伝子産物からミトコンドリア品質管理を考える (2019)
  • Author(s): 松田憲之
  • Organizer: 第二回三融会・武田神経科学シンポジウム
  • Invited
• [Presentation] PINK1, Parkin and the ubiquitin system in TP5 (2019)
  • Author(s): Noriyuki Matsuda
  • Organizer: 5th WPC (5th World Parkinson Congress)
  • Int'l Joint Research / Invited
• [Presentation] ミトコンドリア-リソソーム連携の破綻とパーキンソン病 (2019)
  • Author(s): 松田憲之
  • Organizer: Neuro 2019 (第42回日本神経科学大会 第62回日本神経化学会大会)
  • Invited
• [Presentation] PINK1, Parkin, DJ-1はミトコンドリア品質管理やアルデヒド解毒を介してパーキンソン病を防止する (2019)
  • Author(s): 松田憲之
  • Organizer: 第92回日本生化学会大会
  • Invited
• [Presentation] New role for PINK1/Parkin-mediated ubiquitylation (2019)
  • Author(s): Noriyuki Matsuda
  • Organizer: Singapore Mitochondrial Mini-Symposium 2019
  • Int'l Joint Research / Invited
• [Presentation] リン酸化ユビキチンの発見とマイトファジー制御 (2018)
  • Author(s): 松田憲之
  • Organizer: 第59回 日本植物生理学会年会
  • Invited
• [Presentation] Mitochondria quality control elucidated from Parkinson's disease (2018)
  • Author(s): Noriyuki Matsuda
  • Organizer: Keystone Symposia, joint symposium of Mitochondrial Biology (Z1) and Selective Autophagy (Z2)
  • Int'l Joint Research / Invited
• [Presentation] マイトファジーの破綻と遺伝性パーキンソン病 (2018)
  • Author(s): 松田憲之
  • Organizer: 千里ライフサイエンスセミナー
  • Invited
• [Presentation] How PINK1 and Parkin catalyze mitochondrial ubiquitylation and the ubiquitin chain prevents Parkinson’s disease (2018)
  • Author(s): Noriyuki Matsuda
  • Organizer: 第４１回日本神経科学大会
  • Int'l Joint Research / Invited
• [Presentation] 生化学・細胞・構造の視点から見たPINK1とParkinによるミトコンドリア品質管理 (2018)
  • Author(s): 松田憲之
  • Organizer: 第１８回日本ミトコンドリア学会年会
  • Invited
• [Remarks] ユビキチンがミトコンドリア - ペルオキシソーム間輸送シグナルとして機能する
  • URL: https://www.igakuken.or.jp/topics/2019/1010.html
• [Remarks] 研究Topics:不良ミトコンドリアを分解する新しい仕組みを解明
  • URL: http://www.igakuken.or.jp/topics/2018/0123.html