Involvment of ubiquitin-proteasome system in the pathophsiology of depression

• Project/Area Number: 26860175
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Meijo University
• Principal Investigator: Mouri Akihiro 名城大学, 薬学部, 助教 (20597851)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: うつ / ユビキチン化 / セロトニントランスポーター / MAGE-D1 / ストレスモデル / うつ病 / 動物モデル / 社会的敗北ストレス / 隔離飼育ストレス / 行動解析 / マイクロアレイ解析 / ユビキチン-プロテソーム系

Outline of Final Research Achievements

Here, I clarified involvement of the ubiquitin-proteasome system in the depression by the crosstalk between basic and clinical researches. In the basic research, different expression changes of serotonin transporter and melanoma antigen gene-D1 (MAGE-D1) is observed between social defeat stress and isolation stress during childhood. The behavioral changes by stress responsiveness in the MAGE-D1 knockout mouse were also different between these stresses. Ubiquitin-related genes were changed by isolation stress during childhood. In the clinical research, the ubiquitinated serotonin transporter levels in the platelet was decreased in the patient with the physical disease associated with depression.

Research Products

• [Journal Article] The ubiquitination of serotonin transporter in lymphoblasts derived from fluvoxamine-resistant depression patients. (2016)
  • Author(s): Mouri A, Ikeda M, Koseki T, Iwata N, Nabeshima T.
  • Journal Title: Neurosci Lett. Volume: 617 Pages: 22-6
  • DOI: 10.1016/j.neulet.2016.01.064
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prenatal Nicotine Exposure Impairs the Proliferation of Neuronal Progenitors, Leading to Fewer Glutamatergic Neurons in the Medial Prefrontal Cortex. (2016)
  • Author(s): Aoyama Y, Toriumi K, Mouri A, Hattori T, Ueda E, Shimato A, Sakakibara N, Soh Y, Mamiya T, Nagai T, Kim HC, Hiramatsu M, Nabeshima T, Yamada K.
  • Journal Title: Neuropsychopharmacology Volume: 41(2) Issue: 2 Pages: 578-89
  • DOI: 10.1038/npp.2015.186
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of SHATI/NAT8L decreases the N-acetylaspartate content in the brain and induces behavioral deficits, which can be ameliorated by administering N-acetylaspartate. (2015)
  • Author(s): Toriumi K, Mamiya T, Song Z, Honjo T, Watanabe H, Tanaka J, Kondo M, Mouri A, Kim HC, Nitta A, Fukushima T, Nabeshima T.
  • Journal Title: Eur Neuropsychopharmacol. Volume: 25(11) Issue: 11 Pages: 2108-17
  • DOI: 10.1016/j.euroneuro.2015.08.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Thyrotropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction (2014)
  • Author(s): Mouri A, Hoshino Y, Narusawa S, Ikegami K, Mizoguchi H, Murata Y, Yoshimura T, Nabeshima T
  • Journal Title: Psychoneuroendocrinology Volume: 48 Pages: 147-161
  • DOI: 10.1016/j.psyneuen.2014.05.021
  • Peer Reviewed
• [Presentation] 幼若期社会的敗北ストレス負荷によるセロトニントランスポーターの代謝機構への影響 (2015)
  • Author(s): 毛利彰宏、横山美里、肥田裕丈、長谷川章、木村真理、森 大輔、尾崎紀夫、鍋島俊隆、野田幸裕
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2015
  • Place of Presentation: 東京
  • Year and Date: 2015-08-29
• [Presentation] シンポジウム13 グリア-神経相関による精神疾患の発症と病態：統合失調症モデル動物におけるグリアを介した神経発達・伝達の調節機構 (2015)
  • Author(s): 毛利彰宏、肥田裕丈、野田幸裕
  • Organizer: 第88回日本薬理学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-03-18
• [Presentation] 教育セミナー5 妥当性に基づく精神疾患モデルの開発とその臨床応用：うつ病モデル動物としてのMAGE-D1遺伝子欠損マウスの妥当性と診断薬開発の試み (2014)
  • Author(s): 毛利彰宏、野田幸裕、渡辺 研、岩田仲生、尾崎紀夫、鍋島俊隆
  • Organizer: 第24回日本臨床精神神経薬理学会・第44回日本神経精神薬理学会合同年会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-11-21
• [Presentation] 末梢血におけるセロトニントランスポーターの代謝調節と情動性の関連解析 (2014)
  • Author(s): 毛利彰宏、横山美里、木村真理、椿井 朋、肥田裕丈、木村宏之、徳倉達也、吉見 陽、河野直子、國本正子、尾崎紀夫、鍋島俊隆、野田幸裕
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2014
  • Place of Presentation: 大阪
  • Year and Date: 2014-08-30
• [Presentation] シンポジウム6 若手創薬シンポジウム：セロトニントランスポーターの代謝機構に注目したうつ様行動の解明 (2014)
  • Author(s): 毛利彰宏、野田幸裕、横山美里、渡辺 研、岩田仲生、尾崎紀夫、鍋島俊隆
  • Organizer: 生体機能と創薬シンポジウム2014
  • Place of Presentation: 大阪
  • Year and Date: 2014-08-29
• [Presentation] Serotonin transporter ubiquitynation is a potential biomarker for major depressive disorder (2014)
  • Author(s): Toshitaka Nabeshima, Akihiro Mouri, Misato Yokoyama, Naoko Kawano, Akira Yoshimi, Masashi Ikeda, Takayoshi Mamiya, Kiyofumi Yamada, Nakao Iwata, Norio Ozaki, Yukihiro Noda
  • Organizer: 29th CINP World Congress of Neuropsychopharmacology
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2014-06-24