Astrocyte protection by targeting lipid rafts

• Project/Area Number: 24591279
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Fujita Health University
• Principal Investigator: ASAKURA Kunihiko 藤田保健衛生大学, 医学部, 教授 (50333159)
• Co-Investigator(Kenkyū-buntansha): MUTOH Tatsuro 藤田保健衛生大学医学部, 脳神経内科学, 教授 (60190857)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: アクアポリン４ / 視神経脊髄炎 / 脂質ラフト / アストロサイト / 抗アクアポリン４抗体 / 補体 / 治療

Outline of Final Research Achievements

Neuromyelitis optica (NMO)-IgG is highly specific diagnostic marker for NMO and contributes directly to disease pathogenesis. The target antigen of NMO-IgG was identified as aquaporin-4 (AQP4). There ae two major AQP4 isoforms, M1 and M23. We generated M1, M23, and M1/M23 co-expressing astrocyte cell lines. Most of M1 is localized in lipid raft on the membrane; in contrast, M23 is localized in both lipid raft and non-raft fractions when expressed independently. When both M1 and M23 are expressed, the majority of AQP4 is localized in lipid rafts. Cholesterol depletion with methyl-b-cyclodextrin or simvastatin resulted in the relocation of AQP4 from lipid rafts to non-rafts fraction. This change in the localization of AQP4 on membrane significantly reduced complement-dependent cytotoxic effects of NMO-IgG without affecting AQP4 orthogonal arrays. Thus, these data strongly suggest that the targeting of AQP4 in the lipid rafts is closely related to the pathogenic effects of NMO-IgG.

Research Products

• [Journal Article] Lipid rafts and their possible involvements in neuroimmunological disorders. (2015)
  • Author(s): Asakura K, Ueda A, Mutoh T.
  • Journal Title: Frontｉers in Bioscience (Landmark Edition) Volume: 20 Pages: 303-313
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Voriconazole-responsive disseminated nodular lesions on spinal MRI. (2015)
  • Author(s): Hirota S, Ito S, Fukui T, Murate K, Shima S, Kizawa M, Ueda A, Asakura K, Mutoh T.
  • Journal Title: Internal Medicine Volume: 54 Pages: 215-218
  • NAID: 130004903008
  • Peer Reviewed
• [Journal Article] Histone deacetylase inhibitor attenuates neurotoxicology of clioquinol in PC12 cells. (2015)
  • Author(s): Fukui T, Asakura K, Hikichi C, Ishikawa T, Murai R, Hirota S, Murate KI, Kizawa M, Ueda A, Ito S, Mutoh T.
  • Journal Title: Toxicology Volume: 331 Pages: 112-118
  • DOI: 10.1016/j.tox.2015.01.013
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Amyloid β hypothesis in Alzheimer’s disease and neurotoxicity of oligomeric amyloid via glial cells. (2015)
  • Author(s): Asakura K
  • Journal Title: Clinical and Exp Neuroimmunology Volume: 6 Pages: 116-117
  • Open Access
• [Journal Article] Targeting of aquaporin 4 into lipid rafts and its biological significance. (2014)
  • Author(s): Asakura K, Ueda A, Shima S, Ishikawa T, Hikichi C, Hirota S, Fukui T, Ito S, Mutoh T.
  • Journal Title: Ｂｒａｉｎ Ｒｅｓｅａｒｃｈ Volume: 1583 Pages: 237-244
  • DOI: 10.1016/j.brainres.2014.08.014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-neutral glycolipid antibodies in encephalomyeloradiculoneuropathy. (2014)
  • Author(s): Shima S, Kawamura N, Ishikawa T, Masuda H, Iwahara C, Niimi Y, Ueda A, Iwabuchi K, Mutoh T.
  • Journal Title: Neurology Volume: 82 Issue: 2 Pages: 114-118
  • DOI: 10.1212/wnl.0000000000000015
  • Peer Reviewed
• [Journal Article] ウェゲナー肉芽腫症と神経合併症 (2013)
  • Author(s): 朝倉邦彦、武藤多津郎
  • Journal Title: Brain and Nerve Volume: 65 Pages: 1311-1317
• [Journal Article] 左角回から側頭葉にかけての深部白質の脳梗塞で漢字の純粋失書を呈した1例 (2013)
  • Author(s): 石川等真、植田晃広、新美芳樹、引地智加、河村直樹、島さゆり、宮下忠行、伊藤信二、朝倉邦彦、武藤多津郎
  • Journal Title: 脳卒中 Volume: 35 Pages: 306-311
  • NAID: 130004543312
  • Peer Reviewed
• [Presentation] アクアポリン4のチロシンリン酸化反応 (2014)
  • Author(s): 朝倉邦彦, 福井隆男, 廣田政古, 石川等真, 植田晃広, 島さゆり, 伊藤信二, 武藤多津郎.
  • Organizer: 第26回 日本神経免疫学会学術集会
  • Place of Presentation: 石川県金沢市、金沢歌劇座
  • Year and Date: 2014-09-02 – 2014-09-05
• [Presentation] NMO-IgGによる細胞内シグナル伝達への影響 (2014)
  • Author(s): 朝倉邦彦, 福井隆男, 廣田政古, 植田晃広, 島さゆり, 伊藤信二, 武藤多津郎.
  • Organizer: 第56回日本神経学会学術大会
  • Place of Presentation: 福岡県福岡市、福岡国際会議場
  • Year and Date: 2014-05-19 – 2014-05-22
• [Presentation] New Autoantibodies Against Neutral Glycolipids In Encephalomyeloradiculoneuropathy. (2014)
  • Author(s): Mutoh T, Shima S, Ishikawa T, Ueda A, Asakura K.
  • Organizer: The 66th American Academy of Neurology Annual Meeting; Philadelphia
  • Place of Presentation: Philladelphia, USA
  • Year and Date: 2014-04-27 – 2014-04-30
• [Presentation] NMO-IgGによる細胞内シグナル伝達への影響 (2014)
  • Author(s): 武藤多津郎、朝倉邦彦、植田晃広、島さゆり、松本慎二郎、伊藤信二
  • Organizer: 免疫性神経疾患に関する調査研究班研究報告会
  • Place of Presentation: 東京
• [Presentation] 脂質ラフトを標的としたアストロサイト障害抑制 (2013)
  • Author(s): 朝倉邦彦、植田晃広、河村直樹、島さゆり、新美芳樹、武藤多津郎
  • Organizer: 日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] 脂質ラフトを標的としたアストロサイト障害抑制 (2013)
  • Author(s): 朝倉邦彦、植田晃広、河村直樹、島さゆり、新美芳樹、武藤多津郎
  • Organizer: 日本神経免疫学会
  • Place of Presentation: 下関
• [Presentation] AQP4を介したアストロサイト障害機序の解析 (2013)
  • Author(s): 武藤多津郎、朝倉邦彦、河村直樹、植田晃広、新美芳樹、伊藤信二
  • Organizer: 厚生労働省 免疫性神経疾患に関する調査研究班
  • Place of Presentation: 東京
• [Presentation] 生理的アクアポリン4発現系におけるその細胞内局在解析 (2012)
  • Author(s): 朝倉邦彦、植田晃広、木澤真努香、伊藤信二、武藤多津郎
  • Organizer: 神経免疫学会
  • Place of Presentation: 軽井沢