A novel trafficking mechanism regulated by bisecting GlcNAc, an Alzheimer's disease accelerator

• Project/Area Number: 26670148
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Kizuka Yasuhiko 国立研究開発法人理化学研究所, 疾患糖鎖研究チーム, 研究員 (20564743)
• Research Collaborator: SATO Keiko 国立研究開発法人理化学研究所, 疾患糖鎖研究チーム, パートタイマー ; KITAZUME Shinobu 国立研究開発法人理化学研究所, 疾患糖鎖研究チーム, 副チームリーダー (80301753) ; TANIGUCHI Naoyuki 国立研究開発法人理化学研究所, システム糖鎖生物学研究グループ, グループディレクター (90002188) ; NAKANO Miyako 広島大学, 先端物質科学研究科, 准教授 (40397724) ; NAKAJIMA Kazuki 藤田保健衛生大学, 研究支援推進センター, 講師 (10442998)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 糖鎖 / アルツハイマー病 / BACE1 / バイセクト糖鎖 / GnT-III

Outline of Final Research Achievements

The aim of this study is to clarify the mechanisms of Alzheimer's disease (AD) development, focusing on a neural glycan bisecting GlcNAc.
We focused on AD-related protein BACE1 and identified its new interacting partner Clec4g. Furthermore, our data suggest that oxidative stress induced in AD brain upregulates the level of bisecting GlcNAc on BACE1, which could lead to AD development. These findings will be useful to better understand the mechanisms of AD development.

Research Products

• [Int'l Joint Research] Academia Sinica(台湾)
• [Int'l Joint Research] Saarland University(ドイツ)
• [Journal Article] Expression of Neural Glycans and Their Role in Disease (2017)
  • Author(s): Kizuka Y.
  • Journal Title: TIGG Volume: 29 Issue: 165 Pages: E11-E18
  • DOI: 10.4052/tigg.1613.2E
  • NAID: 130005297139
  • Peer Reviewed
• [Journal Article] High-Sensitivity and Low-Toxicity Fucose Probe for Glycan Imaging and Biomarker Discovery (2016)
  • Author(s): Kizuka Y, Funayama S, Shogomori H, Nakano M, Nakajima K, Oka R, Kitazume S, Yamaguchi Y, Sano M, Korekane H, Hsu TL, Lee HY, Wong CH, Taniguchi N.
  • Journal Title: Cell Chem Biol. Volume: 23 Pages: 782-792
  • DOI: 10.1016/j.chembiol.2016.06.010
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Epigenetic regulation of neural N-glycomics (2016)
  • Author(s): Kizuka Y, Nakano M, Miura Y, Taniguchi N.
  • Journal Title: Proteomics Volume: 16 Pages: 2854-2863
  • DOI: 10.1002/pmic.201600053
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Disease-associated glycans on cell surface proteins (2016)
  • Author(s): Takahashi M, Kizuka Y, Ohtsubo K, Gu J, Taniguchi N.
  • Journal Title: Mol Aspects Med. Volume: 51 Pages: 56-70
  • DOI: 10.1016/j.mam.2016.04.008
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Enzymes for N-Glycan Branching and Their Genetic and Nongenetic Regulation in Cancer (2016)
  • Author(s): Kizuka Y, Taniguchi N.
  • Journal Title: Biomolecules Volume: 6
  • DOI: 10.3390/biom6020025
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bisecting GlcNAc modification stabilizes BACE1 protein under oxidative stress conditions. (2016)
  • Author(s): Kizuka Y, Nakano M, Kitazume S, Saito T, Saido TC, Taniguchi N
  • Journal Title: Biochem. J. Volume: 473 Pages: 21-30
  • DOI: 10.1042/bj20150607
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clec4g (LSECtin) interacts with BACE1 and suppresses Aβ generation. (2015)
  • Author(s): Kizuka Y, Kitazume S, Sato K, Taniguchi N
  • Journal Title: FEBS Letters. Volume: 589 Pages: 1418-1422
  • DOI: 10.1016/j.febslet.2015.04.060
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of N-glycans in cancer biomarker, progression and metastasis and therapeutics (2015)
  • Author(s): Naoyuki Taniguchi, Yasuhiko Kizuka
  • Journal Title: Advances in Cancer Research Volume: 126 Pages: 11-51
  • DOI: 10.1016/bs.acr.2014.11.001
• [Presentation] 神経系における糖鎖修飾とアルツハイマー病 (2017)
  • Author(s): 木塚康彦
  • Organizer: 第13回レドックス・ライフイノベーションシンポジウム
  • Place of Presentation: 奈良女子大学（奈良）
  • Year and Date: 2017-03-16
  • Invited
• [Presentation] アルツハイマー病におけるbisecting GlcNAc糖鎖の役割について (2017)
  • Author(s): 木塚康彦
  • Organizer: 新学術領域「神経糖鎖生物学」最終シンポジウム
  • Place of Presentation: JPタワー（名古屋）
  • Year and Date: 2017-03-03
  • Invited
• [Presentation] Bisecting GlcNAc糖鎖修飾とアルツハイマー病に関する研究 (2016)
  • Author(s): 木塚康彦、北爪しのぶ、谷口直之
  • Organizer: 第57回日本生化学会 中国・四国支部例会
  • Place of Presentation: 高知大学（高知）
  • Year and Date: 2016-05-27
  • Invited
• [Presentation] Glyco-redox, a link of glycobiology and redox balance, is implicated in Alzheimer’s disease (2016)
  • Author(s): Kizuka Y., Chienwichai P., Taniguchi N
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Physiological and pathological roles of bisecting GlcNAc (2016)
  • Author(s): Kizuka Y., Nakano M., Kitazume S., Taniguchi N.
  • Organizer: RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, The fifth symposium
  • Place of Presentation: ベルリン（ドイツ）
  • Year and Date: 2016-04-17
  • Int'l Joint Research
• [Presentation] アルツハイマー病を促進させるバイセクト糖鎖 (2016)
  • Author(s): 木塚康彦、北爪しのぶ、谷口直之
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-09
  • Invited
• [Presentation] BACE1のbisecting GlcNAc修飾によるアルツハイマー病の発症メカニズム (2015)
  • Author(s): 木塚康彦、北爪しのぶ、中の三弥子、西道隆臣、橋本康弘、遠藤玉夫、谷口直之
  • Organizer: 第88回日本生化学会大会 第38回日本分子生物学会年会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
  • Invited
• [Presentation] Bisecting GlcNAcによるBACE1の分解制御メカニズム (2015)
  • Author(s): 木塚康彦、中の三弥子、北爪しのぶ、斉藤貴志、西道隆臣、谷口直之
  • Organizer: GlycoTOKYO2015シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2015-10-24
• [Presentation] Bisecting GlcNAc on BACE1 is a Novel Therapeutic Target for Alzheimer’s Disease (2015)
  • Author(s): Kizuka Y, Kitazume S, Nakano M, Saido T, Hashimoto Y, Endo T, Taniguchi N
  • Organizer: XXIII International Symposium on Glycoconjugates.
  • Place of Presentation: Split (Croatia)
  • Year and Date: 2015-09-15
  • Int'l Joint Research
• [Presentation] Bisecting GlcNAc regulates Alzheimer’s Disease development (2015)
  • Author(s): Kizuka Y, Kitazume S, Nakano M, Saido T, Yamaguchi Y, Yoshida M, Hashimoto Y, Endo T, Taniguchi N
  • Organizer: 4th Austria-Japan Seminar for Comparative and Developmental Glycobiology
  • Place of Presentation: Split (Croatia)
  • Year and Date: 2015-09-15
  • Int'l Joint Research
• [Presentation] 神経系糖鎖の発現制御と認知症病態形成における役割についての研究 (2015)
  • Author(s): 木塚康彦
  • Organizer: 第34回日本糖質学会年会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-31
  • Invited
• [Presentation] Bisecting GlcNAcは酸化ストレスによるBACE1の発現誘導を制御する (2015)
  • Author(s): 木塚康彦、北爪しのぶ、谷口直之
  • Organizer: 第2回FCCAシンポジウムFCCAグライコサイエンス若手フォーラム2015
  • Place of Presentation: 東京
  • Year and Date: 2015-07-30
• [Presentation] Bisecting GlcNAc modification is a novel therapeutic target for Alzheimer’s disease (2015)
  • Author(s): Kizuka Y, Kitazume S, Saido T, Nakano M, Ohnuki T, Shirouzu M, Yoshida M, Zegzouti H, Endo T, Taniguchi N
  • Organizer: RIKEN-Max Planck Joint Research Center for Systems Chemical Biology, The 4th symposium
  • Place of Presentation: 神戸
  • Year and Date: 2015-05-11
  • Int'l Joint Research
• [Presentation] High-throughput screening of GnT-III inhibitors using UDP-Glo system to develop a novel drug candidate for Alzheimer’s disease (2014)
  • Author(s): Yasuhiko Kizuka, Shinobu Kitazume, Keiko Sato, Tetsuo Ohnuki, Mutsuko Kukimoto-Niino, Mikako Shirouzu, Minoru Yoshida, Laurie Engel, Hicham Zegzouti, Naoyuki Taniguchi
  • Organizer: SFG & JSCR 2014 Joint Annual Meeting
  • Place of Presentation: Honolulu
  • Year and Date: 2014-11-16 – 2014-11-19
• [Presentation] Bisecting GlcNAc欠損によるアルツハイマー病抑制に関する研究 (2014)
  • Author(s): 木塚康彦、北爪しのぶ、藤縄玲子、斎藤貴志、岩田修永、西道隆臣、中の三弥子、山口芳樹、橋本康弘、Matthias Staufenbiel、初田裕幸、村山繁雄、萬谷博、遠藤玉夫、谷口直之
  • Organizer: 第33回日本糖質学会年会
  • Place of Presentation: 名古屋
  • Year and Date: 2014-08-10 – 2014-08-12