Pathogenesis of tauopathies in terms of protein quality control mechanism

• Project/Area Number: 24591709
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Osaka University
• Principal Investigator: KUDO Takashi 大阪大学, 学内共同利用施設等, 教授 (10273632)
• Co-Investigator(Kenkyū-buntansha): TAGAMI Shinji 大阪大学, 大学院医学系研究科, 助教 (40362735) ; MORIHARA Takashi 大阪大学, 大学院医学家研究科, 助教 (90403196)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: アルツハイマー病 / タウオパチー / 小胞体ストレス / タウ / ユビキチン / CHIP

Outline of Final Research Achievements

We show that ER stress, induced by glucose deprivation or chemicals, increases total endogenous tau protein in cultured neurons and primary cultured neurons. Under ER stress, no significant differences were observed in the transcription f tau, and no differences were observed in the translation of tau with or ithout the 50-untranslated region (50UTR) of tau. In contrast, the degradation rate of tau was decreased by 20% under ER stress. ER stress reduced the binding between tau and carboxyl terminus of Hsc70-interacting protein (CHIP), biquitin E3 ligase for tau. These results suggest that ER stress increases total tau protein and its mechanism is due to the decrease in the binding between tau and CHIP, which delays the degradation of tau protein through the ubiquitin proteasome pathway. This mechanism may provide clue to treatment for tauopathy.

Research Products

• [Journal Article] Fluvoxamine alleviates ER stress via induction of Sigma-1 receptor (2014)
  • Author(s): Omi T, Tanimukai H, Kanayama D, Sakagami Y, Tagami S, Okochi M, Morihara T, Sato M, Yanagida K, Kitasyoji A, Hara H, Imaizumi K, Maurice T, Chevallier N, Marchal S, Takeda M, Kudo T
  • Journal Title: Cell Death and Disease Volume: 5 Issue: 7 Pages: 1-11
  • DOI: 10.1038/cddis.2014.301
  • Peer Reviewed / Open Access
• [Journal Article] Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as as amyloid beta accumulation modifier (2014)
  • Author(s): Morihara, T., Hayashi, N., Yokokoji, M., Akatsu, H., Silverman, MA., Kimura, N., Saito, Y., Suzuki, T., Yanagida, K., Tanaka, T., Kazui, H., Kudo, T., Kodama, TS., Sato, M., Hashimoto, R., Tagami, S., Okochi, M., Ytoh, N., Nishitomi, K., Takamura, H., Katayama, T., Hashizumi, Y., Kimura, R., Kamino, K., Takeda, M
  • Journal Title: Proc. Acad. Natl. Sci. USA Volume: 111 Issue: 7 Pages: 2638-2643
  • DOI: 10.1073/pnas.1307345111
  • Peer Reviewed / Open Access
• [Journal Article] 慢性炎症と認知症－アルツハイマー病を中心に－ (2014)
  • Author(s): 壁下康信、工藤 喬
  • Journal Title: 分子精神医学 Volume: 14 Pages: 23-29
• [Journal Article] 認知症薬物療法の実際 (2014)
  • Author(s): 工藤 喬
  • Journal Title: 日本生物学的精神医学会誌 Volume: 25 Pages: 3-6
  • NAID: 130005395436
• [Journal Article] アルツハイマー病におけるγ‐セクレターゼ阻害薬 (2014)
  • Author(s): 工藤 喬、大河内正康
  • Journal Title: 臨床精神薬理 Volume: 17 Pages: 829-834
• [Journal Article] Role of endoplasmic reticulum stress in light-induced photoreceptor degeneration in mice. (2013)
  • Author(s): Nakanishi T, Shimazawa M, Sugitani S, Kudo T, Imai S, Inokuchi Y, Tsuruma K, Hara H
  • Journal Title: J Neurochem. Volume: 125 Pages: 111-124
  • Peer Reviewed
• [Journal Article] Ｐａｃｌｉｔａｘｅｌ ｉｎｄｕｃｅｓ ｎｅｕｒｏｔｏｘｉｃｉｔｙ ｔｈｒｏｕｇｈ ｅｎｄｏｐｌａｓｍｉｃ ｒｅｔｉｃｕｌｕｍ ｓｔｒｅｓｓ (2013)
  • Author(s): Tamimukai H, Kanayama D, Omi T, Takeda M, Kudo T
  • Journal Title: Biochem Biophys Res Commun Volume: 43 Pages: 151-155
  • Peer Reviewed
• [Journal Article] Involvement of endoplasmic reticulum stress in tauopathy. (2013)
  • Author(s): Sakagami Y, Kudo T, Tanimukai H, Kanayama D, Omi T, Horiguchi K, Okochi M, Imaizumi K, Takeda M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 430(2) Issue: 2 Pages: 500-4
  • DOI: 10.1016/j.bbrc.2012.12.007
  • Peer Reviewed
• [Presentation] Involvement of Endoplasmic Reticulum Stress in Tauopathy (2012)
  • Author(s): SakagamiY, Kudo T, Mitsuda T, Tanimukai H, Okochi M, Imaizumi K, Takeda M
  • Organizer: Alzheimer's Association International Conference
  • Place of Presentation: Vancouver
• [Book] 認知症診療ハンドブック (2012)
  • Author(s): 工藤 喬
  • Total Pages: 200
  • Publisher: 医薬ジャーナル社