Role of the ER stress-related molecule ATF6b in a mouse model of multiple sclerosis

• Project/Area Number: 18K06500
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: Kanazawa University
• Principal Investigator: Hori Osamu 金沢大学, 医学系, 教授 (60303947)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 小胞体ストレス / 脱髄 / 神経炎症 / 神経細胞 / グリア細胞 / 脱髄疾患 / 神経変性 / 炎症応答

Outline of Final Research Achievements

It has been reported that endoplasmic reticulum (ER) stress is involved in the pathology of multiple sclerosis and its experimental animal model, EAE. We, therefore, studied the expression and the possible role of ATF6b, an ER stress-related gene, in a mouse EAE model. When EAE was introduced to WT mice, ATF6b was upregulated in both neurons and oligodendrocytes in the spinal cord. Furthermore, when similar experiments were performed with AFT6b KO mice, the paralysis and demyelination was severer than those in WT mice. These results suggest that ATF6b protects neurons and oligodendrocytes in the pathology of EAE.

Academic Significance and Societal Importance of the Research Achievements

多発性硬化症は原因不明の中枢性炎症性脱髄疾患である。今回の研究から、小胞体ストレスに関係するATF6bという分子がその病態を制御していることが明らかになった。今後、ATF6bの機能を促進したり、量を増加させたりすることで脱髄が抑制できるのではないかと期待される。

Research Products

• [Int'l Joint Research] ニューヨーク大学(米国)
• [Int'l Joint Research] ニューヨーク大学(米国)
• [Journal Article] Abnormal social behavior and altered gene expression in mice lacking NDRG2 (2021)
  • Author(s): Takarada-Iemata Mika、Yoshihara Toru、Okitani Nahoko、Iwata Keiko、Hattori Tsuyoshi、Ishii Hiroshi、Roboon Jureepon、Nguyen Dinh Thi、Fan Qiyan、Tamatani Takashi、Nishiuchi Takumi、Asano Masahide、Hori Osamu
  • Journal Title: Neuroscience Letters Volume: 743 Pages: 135563-135563
  • DOI: 10.1016/j.neulet.2020.135563
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pyramid-Shape Crossings and Intercrossing Fibers Are Key Elements for Construction of the Neural Network in the Superficial White Matter of the Human Cerebrum (2020)
  • Author(s): Shinohara Harumichi、Liu Xiaoliang、Nakajima Riho、Kinoshita Masashi、Ozaki Noriyuki、Hori Osamu、Nakada Mitsutoshi
  • Journal Title: Cerebral Cortex Volume: - Issue: 10 Pages: 5218-5228
  • DOI: 10.1093/cercor/bhaa080
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Direct evidence of the relationship between brain metastatic adenocarcinoma and white matter fibers: A fiber dissection and diffusion tensor imaging tractography study (2020)
  • Author(s): Liu Xiaoliang、Kinoshita Masashi、Shinohara Harumichi、Hori Osamu、Ozaki Noriyuki、Hatta Toshihisa、Honma Satoru、Nakada Mitsutoshi
  • Journal Title: Journal of Clinical Neuroscience Volume: S0967-5852 Pages: 55-61
  • DOI: 10.1016/j.jocn.2020.05.043
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroprotective effects of endogenous secretory receptor for advanced glycation end-products in brain ischemia (2020)
  • Author(s): Simizu Y, Harashima A, Munesue S, Oishi M, Hattori T, Hori O, Kitao Y, Yamamoto H, Leerach N, Nakada M, Yamamoto Y, Hayashi Y
  • Journal Title: Aging Dis Volume: 11 Issue: 3 Pages: 547-547
  • DOI: 10.14336/ad.2019.0715
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of CD38 and supplementation of NAD + attenuate axon degeneration in a mouse facial nerve axotomy model (2020)
  • Author(s): Takaso Y, Noda M, Hattori T, Roboon J, Hatano M, Sugimoto H, Brenner C, Yamamoto Y, Okamoto H, Higashida H, Ito M, Yoshizaki T, Hori O.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 17795-17795
  • DOI: 10.1038/s41598-020-73984-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation (2020)
  • Author(s): A. Nakano-Kobayashi1,*, A. Fukumoto2, A. Morizane2, D. T. Nguyen3, T. M. Le3, K. Hashida3, T. Hosoya4, R. Takahashi5,J. Takahashi2, O. Hori3 and M. Hagiwara1
  • Journal Title: Science Advances Volume: 6 Issue: 46 Pages: 1-12
  • DOI: 10.1126/sciadv.abc1428
  • NAID: 120006898186
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Does the superior fronto-occipital fascicle exist in the human brain? Fiber dissection and brain functional mapping in 90 patients with gliomas (2020)
  • Author(s): Liu Xiaoliang、Kinoshita Masashi、Shinohara Harumichi、Hori Osamu、Ozaki Noriyuki、Nakada Mitsutoshi
  • Journal Title: NeuroImage: Clinical Volume: 25 Pages: 102192-102192
  • DOI: 10.1016/j.nicl.2020.102192
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD38, CD157, and RAGE as Molecular Determinants for Social Behavior. (2019)
  • Author(s): .Higashida H, Hashii M, Tanaka Y, Matsukawa S, Higuchi Y, Gabata R, Tsubomoto M, Seishima N, Teramachi M, Kamijima T, Hattori T, Hori O, Tsuji C, Cherepanov SM, Shabalova AA, Gerasimenko M, Minami K, Yokoyama S, Munesue SI, Harashima A, Yamamoto Y, Salmina AB, Lopatina O.
  • Journal Title: Cells. Volume: 9(1) Issue: 1 Pages: 62-62
  • DOI: 10.3390/cells9010062
  • NAID: 120006859506
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroprotective Effects of Endogenous Secretory Receptor for Advanced Glycation End-products in Brain Ischemia (2019)
  • Author(s): Yu Shimizu, Ai Harashima, Seiichi Munesue, Masahiro Oishi, Tsuyoshi Hattori, Osamu Hori, Yasuko Kitao, Hiroshi Yamamoto, Nontaphat Leerach, Mitsutoshi Nakada, Yasuhiko Yamamoto, Yasuhiko Hayashi
  • Journal Title: Aging and Disease Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Soluble receptor for advanced glycation end products as a biomarker of symptomatic vasospasm in subarachnoid hemorrhage. (2019)
  • Author(s): Aida Y, Kamide T, Ishii H, Kitao Y, Uchiyama N, Nakada M, Hori O.
  • Journal Title: J Neurosurg. Volume: Nov 1 Issue: 1 Pages: 1-9
  • DOI: 10.3171/2019.8.jns191269
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Deletion of CD38 Suppresses Glial Activation and Neuroinflammation in a Mouse Model of Demyelination (2019)
  • Author(s): Roboon Jureepon、Hattori Tsuyoshi、Ishii Hiroshi、Takarada-Iemata Mika、Le Thuong Manh、Shiraishi Yoshitake、Ozaki Noriyuki、Yamamoto Yasuhiko、Sugawara Akira、Okamoto Hiroshi、Higashida Haruhiro、Kitao Yasuko、Hori Osamu
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 13 Pages: 258-258
  • DOI: 10.3389/fncel.2019.00258
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Caspase-1 initiates apoptosis in the absence of gasdermin D (2019)
  • Author(s): Tsuchiya K, Nakajima S, SHosojima S, Nguyen DT, Hattori T, Le TM, Hori O, Mahib MR, Yamaguchi Y, Miura M, Kinoshita T, Kushiyama H, Sakurai M, Shiroishi T, Suda T
  • Journal Title: Nature Communications Volume: In press Issue: 1 Pages: 2091-2091
  • DOI: 10.1038/s41467-019-09753-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Caspase-1 initiates apoptosis in the absence of gasdermin D (2019)
  • Author(s): Tsuchiya K Nakajima S, Hosojima S, Nguyen DT, Hattori T, Le TM, Hori O, Mahib MR, Yamaguchi Y, Miura M, Kinoshita T, Kushiyama H, Sakurai M, Shiroishi T, Suda T
  • Journal Title: Nat Commun Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pre-administration of low-dose methamphetamine enhances movement and neural activity after high-dose methamphetamine administration in the striatum (2019)
  • Author(s): Takeichi T, Hori O, Hattori T, Kiryu K, Zuka M, Kitamura O
  • Journal Title: Neurosci Lett Volume: 703 Pages: 119-124
  • DOI: 10.1016/j.neulet.2019.03.023
  • Peer Reviewed / Open Access
• [Journal Article] Microglial activation in the cochlear nucleus after early hearing loss in rats. (2019)
  • Author(s): Noda M, Hatano M, Hattori T, Takarada-Iemata M, Shinozaki T, Sugimoto H, Ito M, Yoshizaki T, Hori O.
  • Journal Title: Auris Nasus Larynx. Volume: 印刷中 Issue: 5 Pages: 716-723
  • DOI: 10.1016/j.anl.2019.02.006
  • Peer Reviewed / Open Access
• [Journal Article] Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice. (2019)
  • Author(s): Yamamoto Y, Liang M, Munesue S, Deguchi K, Harashima A, Furuhara K, Yuhi T, Zhong J, Akther S, Goto H, Eguchi Y, Kitao Y, Hori O, Shiraishi Y, Ozaki N, Shimizu Y, Kamide T, Yoshikawa A, Hayashi Y, Nakada M, Lopatina O, Gerasimenko M, Komleva Y, Malinovskaya N, Salmina AB, Asano M, Nishimori K, Higashida H et al.,
  • Journal Title: Commun Biol Volume: ２ Issue: 1 Pages: 76-76
  • DOI: 10.1038/s42003-019-0325-6
  • NAID: 120006605138
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of nuclear factor-κB p65 phosphorylation by 3,4-dihydroxybenzalacetone and caffeic acid phenethyl ester. (2018)
  • Author(s): Takakura K, Takatou S, Tomiyama R, Le TM, Nguyen DT, Nakamura Y, Konishi T, Matsugo S, Hori O.
  • Journal Title: J Pharmacol Sci Volume: 137(3) Issue: 3 Pages: 248-255
  • DOI: 10.1016/j.jphs.2018.07.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] N-myc downstream-regulated gene 2 protects blood-brain barrier integrity following cerebral ischemia (2018)
  • Author(s): Takarada-Iemata Mika、Yoshikawa Akifumi、Ta Hieu Minh、Okitani Nahoko、Nishiuchi Takumi、Aida Yasuhiro、Kamide Tomoya、Hattori Tsuyoshi、Ishii Hiroshi、Tamatani Takashi、Le Thuong Manh、Roboon Jureepon、Kitao Yasuko、Matsuyama Tomohiro、Nakada Mitsutoshi、Hori Osamu
  • Journal Title: Glia Volume: 印刷中 Issue: 7 Pages: 1432-1446
  • DOI: 10.1002/glia.23315
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Ndrg2 deficiency ameliorates neurodegeneration in experimental autoimmune encephalomyelitis (2018)
  • Author(s): Le Thuong Manh、Takarada-Iemata Mika、Ta Hieu Minh、Roboon Jureepon、Ishii Hiroshi、Tamatani Takashi、Kitao Yasuko、Hattori Tsuyoshi、Hori Osamu
  • Journal Title: Journal of neurochemistry Volume: 印刷中 Issue: 2 Pages: 139-153
  • DOI: 10.1111/jnc.14294
  • Peer Reviewed / Int'l Joint Research
• [Presentation] アストロサイトCD38による社会性記憶の制 (2021)
  • Author(s): 服部 剛志、堀 修
  • Organizer: 第126回日本解剖学会総会・全国学術集会・第98回日本生理学会大会
• [Presentation] 脳損傷後の小胞体ストレス応答の細胞・時間 (2021)
  • Author(s): 範 啓エン、宝田 美佳、堀 修
  • Organizer: 第126回日本解剖学会総会・全国学術集会・第98回日本生理学会大会
• [Presentation] マウス下垂体血管内皮細胞におけるCD38の発現 (2021)
  • Author(s): 坂賀 綾、堀 修
  • Organizer: 第126回日本解剖学会総会・全国学術集会・第98回日本生理学会大会
• [Presentation] Neuroprotective role of glial ATF6α pathway in optic nerve injury (2019)
  • Author(s): 宝田美佳、堀修
  • Organizer: 第42回日本神経科学大会・第62回日本神経化学会合同年会
• [Presentation] 脳発達と社会性行動におけるアストロサイトCD38の役割 (2019)
  • Author(s): 服部剛志、堀修
  • Organizer: 第49回日本神経精神薬理学会
  • Invited
• [Presentation] DAMPs-dependent neutrophil migration is critical pathology in cerebral vasospasm after SAH (2019)
  • Author(s): 石井宏史、堀修
  • Organizer: 第62回日本脳循環代謝学会
  • Invited
• [Presentation] 脳梗塞後のグリアストレス応答を介した神経血管保護作用 (2019)
  • Author(s): 第42回日本分子生物学会
  • Organizer: 第42回日本分子生物学会
  • Invited
• [Presentation] 脳虚血病態におけるストレス応答性分子の保護的効果 (2018)
  • Author(s): 宝田美佳、堀修
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Presentation] Protective role of NDRG2 in blood-brain barrier integrity following ischemia (2018)
  • Author(s): 宝田美佳、堀修
  • Organizer: International Conference on Neurovascular and Neurodegenerative Diseases
  • Int'l Joint Research / Invited
• [Presentation] アストロサイトCD38による神経発達制御機構 (2018)
  • Author(s): 服部剛志、堀修
  • Organizer: 日本解剖学会 第78回中部支部学術集会
• [Presentation] Peripheral leukocyte accumulation in the brain is critical pathology of cerebral vasospasm/neuronal dysfunction after subdural arachnoid hemorrhage (2018)
  • Author(s): 石井宏史、堀修
  • Organizer: 日本解剖学会 第78回中部支部学術集会
• [Presentation] 視神経傷害後の網膜神経節細胞生存における小胞体ストレス応答ATF6経路の役割 (2018)
  • Author(s): 宝田美佳、堀修
  • Organizer: 日本解剖学会 第78回中部支部学術集会
• [Presentation] The role of CD38 for neuronal and glial development (2018)
  • Author(s): 服部剛志、堀修
  • Organizer: 第61回日本神経化学会
• [Presentation] アストロサイトによる脳梗塞後の血液脳関門制御 (2018)
  • Author(s): 宝田美佳、堀修
  • Organizer: 第61回日本神経化学会
• [Remarks] 金沢大学医薬保険研究域医学系 神経解剖学
• [Remarks]
  • URL: https://med03.w3.kanazawa-u.ac.jp/
• [Remarks] 金沢大学医薬保健研究域医学系 神経解剖学
  • URL: http://med03.w3.kanazawa-u.ac.jp/
• [Remarks]
  • URL: http://med03.w3.kanazawa-u.ac.jp/
• [Patent(Industrial Property Rights)] 脳血管攣縮抑制剤 (2020)
  • Inventor(s): 石井 宏史、堀 修
  • Industrial Property Rights Holder: 石井 宏史、堀 修
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2020-152739
  • Filing Date: 2020
• [Funded Workshop] New Frontier in Neuroscience 2020 (2020)