Molecular mechanisms of glycative stress exposure in patients with schizophrenia

• Project/Area Number: 16H05380
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: ARAI Makoto 公益財団法人東京都医学総合研究所, 精神行動医学研究分野, プロジェクトリーダー (80356253)
• Co-Investigator(Kenkyū-buntansha): 瀧澤 俊也 東海大学, 医学部, 教授 (70197234)
• Research Collaborator: HORIUCHI Yasue ; MIYASHITA Kazuhiro ; TORIUMI Kazuya ; SUZUKI Kazuhiro ; YOSHIKAWA Akane
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2016: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
• Keywords: 糖化 / 統合失調症 / GLO1 / カルボニルストレス / グリケーション / ライフコース / 終末糖化産物 / ライフステージ / 糖化ストレス / 神経科学 / 脳・神経 / トランスレーショナルリサーチ / グリオキサラーゼ / ピリドキサミン / 精神疾患 / バイオマーカー / メタボローム / 酸化ストレス / 遺伝子

Outline of Final Research Achievements

Glycation is the abnormal accumulation of dicarbonyl metabolites leading to increased modification of protein. Glycative stress is a risk factor of various diseases in the life stages, such as diabetes, heart disease, dementia and psychiatric disorders. However, the developmental effects and health-related impacts of glycative stress in the life stages and the molecular basis of these effects are unknown. We found several schizophrenic patients with novel heterozygous frameshift and missense mutations in GLO1 gene with 40-50% and 15-20% reduction of enzymatic activity, respectively. GLO1 is one of enzymes to detoxify reactive carbonyl compounds such as methylglyoxal, preventing the eventual formation of AGEs. In order to evaluate effects of GLO1 deficits on behavior, we generated Glo1 knockout mice and assessed their behavioral phenotypes.

Academic Significance and Societal Importance of the Research Achievements

精神疾患の多くの症例において糖尿病、心血管疾患、肥満など様々な合併症が問題視されている。身体疾患の増悪とも関連のあるカルボニルストレスを軸としてデータ資源を十分に有効活用することは、早期からの精神疾患・身体疾患の予防介入、健康増進に資する予防医学に貢献できるものと考えられ、その社会的意義は高い。統合失調症をはじめとする精神疾患の発症や病態の分子メカニズムを糖化ストレスの観点から理解する事は学術的に意義が高い。

Research Products

• [Journal Article] Three-dimensional alteration of neurites in schizophrenia. (2019)
  • Author(s): Mizutani R, Saiga R, Takeuchi A, Uesugi K, Terada Y, Suzuki Y, De Andrade V, De Carlo F, Takekoshi S, Inomoto C, Nakamura N, Kushima I, Iritani S, Ozaki N, Ide S, Ikeda K, Oshima K, Itokawa M, Arai M.
  • Journal Title: Transl Psychiatry. Volume: 9 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41398-019-0427-4
  • NAID: 40022096063
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 臓器機能論による部品の科学-心はどこまでタンパク質なのか (2019)
  • Author(s): 糸川昌成，宮下光弘，新井誠
  • Journal Title: 精神科 Volume: 34 Pages: 298-305
  • Peer Reviewed
• [Journal Article] ビタミンB6と統合失調症 (2019)
  • Author(s): 新井誠、宮下光弘、吉川茜、鈴木一浩、鳥海和也、堀内泰江、糸川昌成
  • Journal Title: 臨床精神医学 Volume: 48 Pages: 63-73
  • Peer Reviewed
• [Journal Article] カルボニルストレスが亢進する統合失調症患者に対するピリドキサミンの治療可能性 (2018)
  • Author(s): 宮下光弘，高橋克昌，石本佳代，徳永太郎，鈴木一浩，堀内泰江，鳥海和也，岡崎祐士，糸川昌成, 新井誠
  • Journal Title: 精神神経学雑誌 Volume: 120 Pages: 861-867
  • Peer Reviewed / Open Access
• [Journal Article] Spatial Resolution of Pre-reconstruction Raw Images and their Nano-CT Slices. (2018)
  • Author(s): R Mizutani, R Saiga, S Takekoshi, C Inomoto, N Nakamura, M Arai,K Oshima, M Itokawa, Vincent De Andrade, Francesco De Carlo, A Takeuchi,K Uesugi, Y Terada, Y Suzuki.
  • Journal Title: Proceedings of the 14th International Conference on X-ray Microscopy (XRM2018) Volume: 24 Issue: S2 Pages: 358-359
  • DOI: 10.1017/s1431927618014083
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synchrotron Radiation Nanotomography of Biological Soft Tissues (2018)
  • Author(s): R Saiga, S Takekoshi, C Inomoto, N Nakamura, M Arai, K Oshima,M Itokawa, M Hoshino, A Takeuchi, K Uesugi, Y Terada, Y Suzuki, R Mizutani.
  • Journal Title: Proceedings of the 14th International Conference on X-ray Microscopy (XRM2018) Volume: 24 Issue: S2 Pages: 360-361
  • DOI: 10.1017/s1431927618014095
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights. (2018)
  • Author(s): Kushima I, (27名中略）, Hashimoto R,(80名中29番目) , et al.
  • Journal Title: Cell Rep Volume: 24(11) Issue: 11 Pages: 2838-2856
  • DOI: 10.1016/j.celrep.2018.08.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pyridoxamine, A Novel Treatment For Schizophrenia With Enhanced Carbonyl Stress. (2018)
  • Author(s): Itokawa M, Miyashita M, Arai M, Dan T, Takahashi K, Tokunaga T, Ishimoto K, Toriumi K, Ichikawa T, Horiuchi Y, Kobori A, Usami S, Yoshikawa T, Amano N, Washizuka S, Okazaki Y, Miyata T.
  • Journal Title: Psychiatry Clin Neurosci. Volume: 72(1) Issue: 1 Pages: 35-44
  • DOI: 10.1111/pcn.12613
  • Peer Reviewed / Open Access
• [Journal Article] iPS細胞を用いた精神疾患病態モデルの可能性と課題 (2018)
  • Author(s): 堀内泰江，森暁，新井誠，糸川昌成
  • Journal Title: 精神科臨床Legato Volume: 4(1) Pages: 21-24
  • Peer Reviewed
• [Journal Article] 精神疾患治療薬開発の新しいアプローチ－病気と病気でないもの、モノかコトか－ (2018)
  • Author(s): 糸川昌成，新井誠
  • Journal Title: バイオサイエンスとインダストリー Volume: 76(2) Pages: 120-126
  • NAID: 40021512193
  • Peer Reviewed
• [Journal Article] 新しい治療の糸口：カルボニルストレス (2018)
  • Author(s): 糸川昌成，新井誠，宮田敏男
  • Journal Title: 日経サイエンス Volume: 1 Pages: 54-62
  • Peer Reviewed
• [Journal Article] Identification of an argpyrimidine-modified protein in human red blood cells from schizophrenic patients: A possible biomarker for diseases involving carbonyl stress (2017)
  • Author(s): Ishida Y.I, Kayama T, Kibune Y, Nishimoto S, Koike S, Suzuki T, Horiuchi Y, Miyashita M, Itokawa M, Arai M, Ogasawara Y
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 493 Issue: 1 Pages: 573-577
  • DOI: 10.1016/j.bbrc.2017.08.150
  • Peer Reviewed / Open Access
• [Journal Article] 生物学と統合失調症．「統合失調症」再考 (2017)
  • Author(s): 糸川昌成，新井誠，針間博彦，齋藤正彦
  • Journal Title: 精神医学 Volume: 59(11) Pages: 1037-1044
  • Peer Reviewed
• [Journal Article] Peripheral Soluble RAGE Levels in Schizophrenia (2017)
  • Author(s): M Miyashita, K Toriumi, Y Horiuchi, K Suzuki, M Itokawa, M Arai
  • Journal Title: IMARS HIGHLIGHTS Volume: 12(5) Pages: 5-9
  • Peer Reviewed
• [Journal Article] 統合失調症スペクトラム障害および他の最新病性障害群 カルボニルストレス (2017)
  • Author(s): 新井誠、宮下光弘、鳥海和也、堀内泰江、糸川昌成
  • Journal Title: 精神医学症候群（第2版）別冊日本臨床 新領域別症候群シリーズ Volume: 37 Pages: 363-367
  • Peer Reviewed
• [Journal Article] High-resolution copy number variation analysis of schizophrenia in Japan. (2017)
  • Author(s): Kushima I, Aleksic B, Nakatochi M, Shimamura T, Shiino T, Yoshimi A, Kimura H, Takasaki Y, Wang C, Xing J, Ishizuka K, Oya-Ito T, Nakamura Y, Arioka Y, Maeda T, Yamamoto M, Yoshida M, Noma H, Hamada S, Morikawa M, Uno Y, Okada T, Iidaka T, Iritani S, Yamamoto T,
  • Journal Title: Molecular Psychiatry Volume: 22 Issue: 3 Pages: 430-440
  • DOI: 10.1038/mp.2016.88
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Music-evoked emotions in schizophrenia (2016)
  • Author(s): Abe D, Arai M, Itokawa M.
  • Journal Title: Schizophr Res. Volume: S0920-9964(16) Pages: 30587-4
  • DOI: 10.1016/j.schres.2016.12.013
  • Peer Reviewed / Open Access
• [Journal Article] The regulation of soluble receptor for AGEs contributes to carbonyl stress in schizophrenia. (2016)
  • Author(s): Miyashita M, Watanabe T, Ichikawa T, Toriumi K, Horiuchi Y, Kobori A, Kushima I, Hashimoto R, Fukumoto M, Koike S, Ujike H, Arinami T, Tatebayashi Y, Kasai K, Takeda M, Ozaki N, Okazaki Y, Yoshikawa T, Amano N, Washizuka S, Yamamoto H, Miyata T, Itokawa M, Yamamoto Y, Arai M.
  • Journal Title: Biochem Biophys Res Commun Volume: 479(3) Issue: 3 Pages: 447-452
  • DOI: 10.1016/j.bbrc.2016.09.074
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Determination of methylglyoxal in human blood plasma using fluorescence high performance liquid chromatography after derivatization with 1,2-diamino-4,5-methylenedioxybenzene. (2016)
  • Author(s): Ogasawara Y, Tanaka R, Koike S, Horiuchi Y, Miyashita M, Arai M.
  • Journal Title: J Chromatogr B Analyt Technol Biomed Life Sci. Volume: 1029-1030 Pages: 102-5
  • DOI: 10.1016/j.jchromb.2016.07.019
  • Peer Reviewed / Open Access
• [Journal Article] カルボニルストレス性統合失調症患者由来iPS細胞を用いた統合失調症病態解明 (2016)
  • Author(s): 堀内泰江, 宮下光弘, 糸川昌成, 新井誠
  • Journal Title: 分子精神医学 Volume: 16(4) Pages: 15-21
  • Acknowledgement Compliant
• [Journal Article] 統合失調症におけるカルボニルストレス (2016)
  • Author(s): 宮下光弘、堀内泰江、新井誠、糸川昌成.
  • Journal Title: 生体の科学 Volume: 67(5) Pages: 484-485
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] 糖化ストレスマーカーと統合失調症 (2016)
  • Author(s): 新井誠、宮下光弘、小堀晶子、堀内泰江、鳥海和也、糸川昌成.
  • Journal Title: 生物学的精神医学会誌 Volume: 27(1) Pages: 8-14
  • NAID: 130006100373
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Beneficial life course intervention in critical and sensitive periods for glycation, oxidative stress, and nutritional epidemiology (2019)
  • Author(s): M Arai
  • Organizer: 19th TOKYO IGAKUKEN International Symposium
  • Int'l Joint Research / Invited
• [Presentation] Susceptibility to carbonyl stress in schizophrenia derived neural cellsderived neural cells. (2018)
  • Author(s): Y Horiuchi, M Ishikawa, S Koike, A Mori, K Toriumi, N Obata, M Miyashita, M Ishikawa, Y Ogasawara, H. Okano, M. Arai
  • Organizer: Society for Neuroscience 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] Behavioral phenotype of glyoxalase 1 knockout mice. (2018)
  • Author(s): K Suzuki, K Ttoriumi, Y Horiuchi, M Miyashita, M Itokawa, M. Arai
  • Organizer: Society for Neuroscience 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] Pyridoxamine, a novel treatment for negative symptoms of schizophrenia. (2018)
  • Author(s): M Arai, M. Miyashita, K. Toriumi, Y Horiuchi, A kobori, M Itokawa
  • Organizer: Society for Neuroscience 2018 Annual Meeting
  • Int'l Joint Research
• [Presentation] Pyridoxamine, a novel treatment for negative symptoms of schizophrenia (2018)
  • Author(s): M Arai, M Miyashita, T Dan, K Toriumi, Y Horiuchi, K Suzuki, T Miyata, M Itokawa.
  • Organizer: 13th International Symposium on The Maillard reaction
  • Int'l Joint Research
• [Presentation] Effect of vitamin B6 deficiency on mouse behavior and monoaminergic system (2018)
  • Author(s): K Toriumi, M Miyashita, Y Horiuchi, A Kobori, I Nohara, Y Shimada, M Hama, N Obata, M Itokawa, M Arai.
  • Organizer: 13th International Symposium on The Maillard reaction
  • Int'l Joint Research
• [Presentation] 統合失調症における神経細胞の構造変化 (2018)
  • Author(s): 刀さくら，佐藤夏菜，竹腰進，井野元智恵，中村直哉，新井誠，大島健一，糸川昌成，鳥居洋太，久島周，入谷修司，尾崎紀夫，竹内晃久，上杉健太郎，寺田靖子，鈴木芳生，Vincent De Andrade, Francesco De Carlo,, 雑賀里乃，水谷隆太
  • Organizer: 第91回日本生化学会
• [Presentation] A challenging step forward in the development of truly pre-emptive sugar chain information trajectory (2018)
  • Author(s): 新井誠
  • Organizer: 第91回日本生化学会
  • Invited
• [Presentation] Schizophrenia and Advanced glycation end products (2018)
  • Author(s): 新井誠
  • Organizer: 第91回日本生化学会
  • Invited
• [Presentation] Carbonyl stress in mood disorder. (2018)
  • Author(s): M Miyashita, K Suzuki, Y Horiuchi, K Toriumi, A Yoshikawa, M Egoshi, A Kobori, A Imai, Y Nagase, K Yuzawa, S Takizawa, S Washizuka, M Itokawa, M Arai
  • Organizer: 第40回日本生物学的精神医学会・第61回日本神経化学会大会合同大会
• [Presentation] カルボニルストレス (2018)
  • Author(s): 新井誠
  • Organizer: 第13回日本統合失調症学会
  • Invited
• [Presentation] カルボニルストレスによる神経分化異常の分子病態 (2018)
  • Author(s): 豊島学，大西哲生，新井誠，糸川昌成，岡野栄之，吉川武男
  • Organizer: 第13回日本統合失調症学会
• [Presentation] Administration of high-dose pyridoxamine to adult mice (2017)
  • Author(s): M Arai, K Toriumi, M Miyashita, Y Horiuchi, I Nohara, N Obata, G Konopka, M Itokawa, T Dan, T Miyata
  • Organizer: WPA XVII WORLD CONGRESS OF PSYCHIATRY
  • Int'l Joint Research
• [Presentation] Effect of deficiency of vitamin B6 on mouse behavior and monoaminergic system (2017)
  • Author(s): K Toriumi, M Miyashita, Y Horiuchi, I Nohara, N Obata, G Konopka, M Itokawa, T Dan, T Miyata , M Arai
  • Organizer: WPA XVII WORLD CONGRESS OF PSYCHIATRY
  • Int'l Joint Research
• [Presentation] Pyridoxamine, a novel treatment for negative symptoms of schizophrenia (2017)
  • Author(s): M Miyashita, M Arai, T Dan, K Toriumi, Y Horiuchi, A Kobori, K Suzuki, M Itokawa, T Miyata
  • Organizer: WPA XVII WORLD CONGRESS OF PSYCHIATRY
  • Int'l Joint Research
• [Presentation] 思春期の心身の健康と生活習慣行動：コホートへの糖化・酸化ストレスマーカー導入 (2017)
  • Author(s): 新井誠
  • Organizer: 第21回日本精神保健・予防学会
  • Invited
• [Presentation] iPS細胞から見える統合失調症の病理と今後の展開 (2017)
  • Author(s): 豊島学，赤松和士，岡田洋平，大西哲生，新井誠，糸川昌成，岡野栄之，吉川武男
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会
• [Presentation] グリオキサラーゼI欠損マウス脳内のメチルグリオキサールの測定 (2017)
  • Author(s): 小池伸，西本翔一，川村久美子，鳥海和也，新井誠，小笠原裕樹
  • Organizer: 第39回日本生物学的精神医学会・第47回日本神経精神薬理学会
• [Presentation] Carbonyls stress and Schizophrenia (2016)
  • Author(s): M Arai
  • Organizer: 14th IGAKUKEN International Symposium
  • Place of Presentation: 東京都医学総合研究所（東京都世田谷区）
  • Int'l Joint Research
• [Presentation] 私にとっての統合失調症研究を通じて～過去・現在・未来～ (2016)
  • Author(s): 新井誠
  • Organizer: 第26回日本メイラード学会
  • Place of Presentation: つくば国際会議場（茨城県つくば市）
  • Invited
• [Presentation] カルボニルストレスが亢進する統合失調症に対するピリドキサミン大量療法の効果の検証 (2016)
  • Author(s): 宮下光弘、新井誠、鳥海和也、堀内泰江、市川智恵、小堀晶子、高橋克昌、徳永太郎、石本佳代、湯澤公子、宇佐美慧、吉川武男、岡崎祐士、鷲塚伸介、天野直二、滝澤俊也、宮田敏男、糸川昌成．
  • Organizer: 第38回日本生物学的精神医学会、第59回日本神経化学会合同年会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
• [Remarks] 東京都医学総合研究所 統合失調症プロジェクト
  • URL: http://www.igakuken.or.jp/project/detail/schizo-dep.html
• [Remarks] 東京都医学総合研究所 精神行動医学研究分野 統合失調症プロジェクト
  • URL: http://www.igakuken.or.jp/schizo-dep/member.html
• [Remarks] 公益財団法人 東京都医学総合研究所
  • URL: http://www.igakuken.or.jp/
• [Remarks] 公益財団法人 東京都医学総合研究所 統合失調症プロジェクト
  • URL: http://www.igakuken.or.jp/schizo-dep/
• [Funded Workshop] 19th TOKYO IGAKUKEN International Symposium (2019)