Protective roles of ATF6 and ATF4 in the mouse model of stroke

• Project/Area Number: 24500419
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Kanazawa University
• Principal Investigator: KITAO Yasuko 金沢大学, 医学系, 協力研究員 (00019613)
• Co-Investigator(Kenkyū-buntansha): HORI Osamu 金沢大学, 医学系, 教授 (60303947)
• Co-Investigator(Renkei-kenkyūsha): TAKARADA Mika 金沢大学, 医学系, 助教 (40565412)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 脳虚血 / 小胞体ストレス / アストロサイト / 脳梗塞 / 神経細胞死 / ＡＴＦ６ / アストログリア / 脳梗塞モデル

Outline of Final Research Achievements

To dissect the role of the unfolded protein response (UPR) in brain ischemia, we investigated the relevance of ATF6α, a master transcriptional factor in the UPR, after middle cerebral artery occlusion (MCAO) in mice. Enhanced expression of GRP78, a downstream molecular chaperone of ATF6α, was observed in the peri-infarct region of wild-type mice after MCAO. Analysis using wild-type and Atf6α-/- mice revealed a larger infarct volume and increased cell death in the peri-ischemic region of Atf6α-/- mice 5 days after MCAO. These phenotypes in Atf6α-/- mice were associated with reduced levels of astroglial activation/glial scar formation, and a spread of tissue damage into the non-infarct area. Further analysis in mice and cultured astrocytes revealed that STAT3-GFAP signaling was diminished in Atf6α-/- astrocytes. These results suggest a critical role of the UPR for regulating astroglial activation and neuronal survival after brain ischemia.

Research Products

• [Journal Article] Deletion of Atf6α impairs astroglial activation and enhances neuronal death after brain ischemia in mice. (2015)
  • Author(s): Yoshikawa A, KamideT, Hashida K, Ta HM, Inahata Y, Takarada-Iemata M, Hattori T, Mori K, Takahashi R, Matsuyama T, Hayashi Y, Kitao Y, Hori O
  • Journal Title: J Neurochem. Volume: 132(3) Issue: 3 Pages: 342-53
  • DOI: 10.1111/jnc.12981
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Anxiety- and depression-like behavior in mice lacking the CD157/BST1 gene, a risk factor for Parkinson's disease. (2014)
  • Author(s): Lopatina O, Yoshihara T, Nishimura T, Zhong J, Akther S, Fakhrul AA, Liang M, Higashida C, Sumi K, Furuhara K, Inahata Y, Huang JJ, Koizumi K, Yokoyama S, Tsuji T, Petugina Y, Sumarokov A, Salmina AB, Hashida K, Kitao Y, Hori O, Asano M, Kitamura Y, Kozaka T, Shiba K, Zhong F, Xie MJ, Sato M, Ishihara K, Higashida H.
  • Journal Title: Front Behav Neurosci Volume: 8 Pages: 1-18
  • DOI: 10.3389/fnbeh.2014.00133
  • Peer Reviewed / Open Access
• [Journal Article] Deletion of N-myc downstream-regulated gene 2 attenuates reactive astrogliosis and inflammatory response in a mouse model of cortical stab injury. (2014)
  • Author(s): Takarada-Iemata M, Kezuka D, Takeichi T, Ikawa M, Hattori T, Kitao Y, Hori O.
  • Journal Title: J Neurochem. Volume: 印刷中 Issue: 3 Pages: 374-87
  • DOI: 10.1111/jnc.12729
  • NAID: 120005478796
  • Peer Reviewed
• [Presentation] The effect of endoplasmic reticulum (ER) stress on STAT3-dependent astroglia l activation after stroke (2014)
  • Author(s): 堀 修、 北尾 康子
  • Organizer: 第87回日本生化学会大会 シンポジウム
  • Place of Presentation: 京都国際会議場（京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] ATF6αの欠損は脳虚血後のアストロサイト活性化を抑制し、神経細胞死を増大させる (2014)
  • Author(s): 堀 修、北尾 康子
  • Organizer: 第36回日本生物学的精神医学会 第 57 回日本神経化学会 シンポジウム
  • Place of Presentation: 奈良県文化会館（奈良市）
  • Year and Date: 2014-09-26
  • Invited
• [Presentation] Deletion of ATF6α causes glial death and delayed neuronal damage after middle cerebral artery occlusion in mice (2013)
  • Author(s): 北尾 康子
  • Organizer: neuro2013
  • Place of Presentation: 京都府 京都国際会議場
• [Presentation] 中枢神経系における小胞体ストレス応答(UPR)の重要性 (2012)
  • Author(s): 堀 修
  • Organizer: 第24回日本脳循環代謝学会
  • Place of Presentation: 広島県 リーガロイヤルホテル広島
  • Invited
• [Presentation] Deletion of ATF6 alfacauses glial death and delayed neuronal damage after middle cereberal artery
  • Author(s): Yasuko Kitao, Osamu Hori
  • Organizer: Neuro 2013
  • Place of Presentation: 京都国際会議場 京都
• [Remarks] 金沢大学医薬保健研究域医学系 神経分子標的学
  • URL: http://med03.w3.kanazawa-u.ac.jp/