The effect of ATF6 deletion on ALS pathology

• Project/Area Number: 26430069
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Kanazawa University
• Principal Investigator: 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): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 神経変性 / 小胞体ストレス

Outline of Final Research Achievements

To dissect the role of the unfolded protein response (UPR) in the pathology of amyotrophic lateral sclerosis (ALS), we crossed ALS (SOD G93A Tg) mice with Atf6α-/- mice, the latter of which lack ATF6a, a major sensor in the UPR. Analysis using ALS and ALS/Atf6α-/- mice revealed the onset time of ALS was significantly earlier in ALS/Atf6α-/- mice, but the life span was not significantly different between two genotypes. Consistent with these results, higher levels of SOD aggregation was observed in ALS/Atf6α-/- mice before the onset, while lower levels of activation was observed in Atf6α-/- mouse-derived microglia, compared with wild-type mouse-derived microglia. These results suggest the time- and cell type-specific regulation of ATF6 may play the important role in the pathology of ALS.

Research Products

• [Journal Article] CD38 positively regulates postnatal development of astrocytes cell-autonomously and oligodendrocytes non-cell-autonomously. (2017)
  • Author(s): Hattori T, Kaji M, Ishii H, Jureepon R, Takarada-Iemata M, Ta HM, Le TM, Konno A, Hirai H, Shiraishi Y, Ozaki N, Yamamoto Y, Okamoto H, Yokoyama S, Higashida H, Kitao Y, Hori O.
  • Journal Title: Glia Volume: 印刷中 Issue: 6 Pages: 974-989
  • DOI: 10.1002/glia.23139
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A dibenzoylmethane derivative inhibits lipopolysaccharide-induced NO production in mouse microglial cell line BV-2. (2017)
  • Author(s): Takano K, Ishida N, Kawabe K, Moriyama M, Hibino S, Choshi T, Hori O, Nakamura Y.
  • Journal Title: Neurochem Int. Volume: 印刷中 Pages: 126-131
  • DOI: 10.1016/j.neuint.2017.04.002
  • NAID: 120007018399
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis. (2016)
  • Author(s): Ta HM, Le TM, Ishii H, Takarada-Iemata M, Hattori T, Hashida K, Yamamoto Y, Mori K, Takahashi R, Kitao Y, Hori O.
  • Journal Title: Journal of Neurochemistry Volume: 139 Issue: 6 Pages: 1124-1137
  • DOI: 10.1111/jnc.13714
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cyclic ADP-ribose as an endogenous inhibitor of the mTOR pathway downstream of dopamine receptors in the mouse striatum. (2016)
  • Author(s): Higashida H, Kamimura SY, Inoue T, Hori O, Islam MS, Lopatina O, Tsuji C.
  • Journal Title: J Neural Transm (Vienna). Volume: 印刷中 Issue: 1 Pages: 17-24
  • DOI: 10.1007/s00702-016-1666-7
  • NAID: 120005971992
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Deletion of Atf6α enhances kainate-induced neuronal death in mice (2016)
  • Author(s): Kezuka D, Tkarada-Iemata M, Hattori T, Mori K, Takahashi R, Kitao Y, Hori O
  • Journal Title: Neurochem Int. Volume: 92 Pages: 67-74
  • DOI: 10.1016/j.neuint.2015.12.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Deletion of Herpud1 Enhances Heme Oxygenase-1 Expression in a Mouse Model of Parkinson's Disease (2016)
  • Author(s): Le TM, Hashida K, Ta HM, Takarada-Iemata M, Kokame K, Kitao Y, Hori O
  • Journal Title: Parkinsons Dis. Volume: 1 Pages: 1-9
  • DOI: 10.1155/2016/6163934
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism. (2015)
  • Author(s): Kitao Y, Ageta-Ishihara N, Takahashi R, Kinoshita M, Hori O.
  • Journal Title: F1000Res. Volume: 4 Pages: 130-130
  • DOI: 10.12688/f1000research.6386.1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] Deletion of Herp Enhances Heme Oxygenase-1 Expression in a Mouse Model of Parkinson’s Disease (2017)
  • Author(s): Le Manh Thuong, Ta Minh Hieu, Yasuko Kitao, Osamu Hori
  • Organizer: 第122回日本解剖学会総会全国学術集会
  • Place of Presentation: 長崎大学
  • Year and Date: 2017-03-28
• [Presentation] A role of CD38 in Cuprizone-induced Demyelination (2017)
  • Author(s): Roboon Jureepon, Tsuyoshi Hattori, Osamu Hori
  • Organizer: 第122回日本解剖学会総会全国学術集会
  • Place of Presentation: 長崎大学
  • Year and Date: 2017-03-28
• [Presentation] Protective roles of ATF6alpha in optic nerve crush injury, a model of neurodegeneration (2016)
  • Author(s): Mika Takarada-Iemata, Yoshiki Koriyama, Kazutoshi Mori, Ryosuke Takahashi, Yasuko Kitao, Osamu Hori
  • Organizer: 第59回日本神経化学会大会/第38回日本生物学的精神医学会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2016-09-08
• [Presentation] Atf6α deficiency suppresses microglial activation and ameliorates pathology of experimental autoimmune encephalomyelitis (2016)
  • Author(s): Ta Minh Hieu, Osamu Hori
  • Organizer: 第59回日本神経化学会大会/第38回日本生物学的精神医学会
  • Place of Presentation: 福岡国際会議場
  • Year and Date: 2016-09-08
• [Presentation] Protective effects of ATF6alpha in a mouse model of optic nerve injury (2015)
  • Author(s): Yoshiki Koriyama, Mika Takarada-Iemata, Tsuyoshi Hattori, Yasuko Kitao, Osamu Hori
  • Organizer: 第38回 日本神経科学大会
  • Place of Presentation: 神戸国際展示場
  • Year and Date: 2015-07-29
• [Presentation] The role of CD38, an Autism Spectrum Disorder (ASD)-associated molecule, in the development of glial cells (2015)
  • Author(s): Tsuyoshi Hattori, Mika Takarada-Iemata, Yasuhiko Yamamoto, Hiroshi Okamoto, Haruhiro Higashida, Osamu Hori
  • Organizer: 第38回 日本神経科学大会
  • Place of Presentation: 神戸国際展示場
  • Year and Date: 2015-07-29
• [Presentation] The effect of endoplasmic reticulum (ER) stress on STAT3-dependent astroglia l activation after stroke (2014)
  • Author(s): 堀 修
  • 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
  • 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: 2014-09-29 – 2014-09-30
  • Invited
• [Remarks] 金沢大学医薬保健研究域医学系 神経解剖学 HP
  • URL: http://med03.w3.kanazawa-u.ac.jp/
• [Remarks] 大脳皮質の発達に重要な遺伝子を解明！
  • URL: https://www.kanazawa-u.ac.jp/rd/44946
• [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/