分子機構研究

メンバー

リーダー 研究副部長 萬谷 博
研究員 赤阪啓子、今江理恵子

キーワード

アルツハイマー病、個体老化、蛋白質分解、糖鎖、糖蛋白質、神経疾患、筋疾患、認知症、老化関連疾患、老化モデルマウス(Klotho)

主な研究

  1. 認知症における糖鎖の解析
  2. 老化モデルマウスを用いた老化機構の解明
  3. 神経筋維持に関連する糖鎖機能の解明

研究紹介

  1. 認知症における糖鎖関連遺伝子の発現変化を網羅的に解析し、どのような遺伝子が関与するかを明らかにします。また、Aβ産生機構と糖鎖の関連を解析し、新たな治療および予防法の開発を目指します。
  2. 老化モデルマウス(Klotho)における責任遺伝子産物の生理機能の解明を目指します。さらに、老化モデルマウスで得られた研究成果の自然老化マウスでの検証および老化関連疾患との関連性を明らかにします。
  3. 神経や筋肉における糖鎖の生理機能や生合成機構を解明し、老化や疾患に伴う変化の実体と病態との関連性を明らかにします。

生命の設計図であるゲノムの遺伝子情報は翻訳されてタンパク質が作られますが、半数以上のタンパク質はこのままではまだ働きが不十分で、そこにリン酸や糖鎖というものがくっついてリン酸化タンパク質や糖タンパク質となり初めて機能的に働きます。これをタンパク質の翻訳後修飾といい、生物のさまざまな機能にかかわっています。本研究グループは細胞どうしの認識や細胞内外の情報伝達において重要な役割を果たしているタンパク質の翻訳後修飾に焦点を当て、老化に伴う機能変化の解明および老化に伴う病態の解明を目指しています。

主要文献

【英文】

  1. Nishihara, R., Kobayashi, K., Imae, R., Tsumoto, H., Manya, H., Mizuno, M., Kanagawa, M., Endo, T., Toda, T.: Cell endogenous activities of fukutin and FKRP coexist with the ribitol xylosyltransferase, TMEM5. Biochem. Biophys. Res. Commun., 2018, 497, 1025-1030
  2. Manya, H., Endo, T.: Glycosylation with ribitol-phosphate in mammals: New insights into the O-mannosyl glycan. Biochim. Biophys. Acta., 1861(10), 2462-2472, 2017
  3. Kanagawa, M., Manya, H.: Tatsushi Toda and Tamao Endo win 107th Japan Academy Prize. Glycobiology, 27(7), 599-600, 2017
  4. Yamashita, K. et al.: Experimental phase determination with selenomethionine or mercury-derivatization in serial femtosecond crystallography. IUCrJ, 4, 639-647, 2017
  5. Nagae, M., Mishra, S.K., Neyazaki, M., Oi, R., Ikeda, A., Matsugaki, N., Akashi, S., Manya, H., Mizuno, M., Yagi, H., Kato, K., Senda, T., Endo, T., Nogi, T., Yamaguchi, Y.: 3D structural analysis of Protein O-Mannosyl Kinase POMK, a causative gene product of dystroglycanopathy. Genes Cells, 2017, 22, 348-359
  6. Akasaka-Manya, K., Kawamura, M., Tsumoto, H., Saitoh, Y., Tachida, Y., Kitazume, S., Hatsuta, H., Miura, Y., Hisanaga, S., Murayama, S., Hashimoto, Y., #Manya, H., #Endo, T.: Excess APP O-glycosylation by GalNAc-T6 decreases Aβ production. J. Biochem., 161(1), 99-111, 2017 (#co-senior authors)
  7. Manya, H., Yamaguchi, Y., Kanagawa, M., Kobayashi, K., Tajiri, M., Akasaka-Manya, K., Kawakami, H., Mizuno, M., Wada, Y., Toda, T., Endo, T.: The muscular dystrophy gene TMEM5 encodes a ribitol β1,4-xylosyltransferase required for the functional glycosylation of dystroglycan. J. Biol. Chem., 291(47), 24618-24627, 2016
    (プレスリリース:http://www.tmghig.jp/research/release/cms_upload/press20161017.pdf
  8. Kuwabara, N., Manya, H., Yamada, T., Tateno, T., Kanagawa, M., Kobayashi, K., Akasaka-Manya, K., Hirose, Y., Mizuno, M., Ikeguchi, M., Toda, T., Hirabayashi, J., Senda, T., #Endo, T., #Kato, R.: Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of a-dystroglycan. Proc. Natl. Acad. Sci. USA, 113 (33), 9280-9285, 2016 (#co-senior authors)
    (プレスリリース: http://www.tmghig.jp/research/release/cms_upload/press20160805.pdf
  9. *Yang, H., *Manya, H., Kobayashi, K., Jiao, H., Fu, X., Xiao, J., Li, X., Wang, J., Jiang, Y., Toda, T., Endo, T., Wu, X., Xiong, H.: Analysis of phenotype, enzyme activity and genotype of Chinese patients with POMT1 mutation. J. Hum. Genet., 61(8), 753-759, 2016 (*co-first authors)
  10. Akasaka-Manya, K., Manya, H., Endo, T.: Function and change with aging of a-klotho in the kidney. Klotho, Vitam. Horm., vol. 101 (Gerald Litwack ed.), Academic Press, pp 239-256, 2016
  11. *Kanagawa, M., *Kobayashi, K., *Tajiri, M., *Manya, H., *Kuga, A., Yamaguchi, Y., Akasaka-Manya, K., Furukawa, J., Mizuno, M., Kawakami, H., Shinohara, Y., #Wada, Y., #Endo, T., #Toda, T.: Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy. Cell Rep., 14(9), 2209-2223, 2016 (*co-first / #co-senior authors)
    (プレスリリース: http://www.tmghig.jp/research/release/cms_upload/press20160229.pdf
  12. Xu, M., Yamada, T., Sun, Z., Eblimit, A., Lopez, I., Wang, F., Manya, H., Xu, S., Zhao, L., Li, Y., Kimchi, A., Sharon, D., Sui, R., #Endo, T., #Koenekoop, R.K., #Chen, R. : Mutations in POMGNT1 cause non-syndromic retinitis pigmentosa. Hum. Mol. Genet., 25(8), 1479-1488, 2016 (#co-senior authors)
    (プレスリリース:http://www.tmghig.jp/research/release/cms_upload/press20160222.pdf
  13. Riemersma M.,, Sean Froese, D., van Tol, W., Engelke, U.F., Kopec, J. van Scherpenzeel, M., Ashikov, A., Krojer, T., von Delft, F., Tessari, M., Buczkowska, A., Swiezewska, E., Jae, L.T., Brummelkamp, T.R., Manya, H., Endo, T., van Bokhoven, H., Yue, W.W., Lefeber, D.J. : Human ISPD is a cytidyltransferase required for dystroglycan O-mannosylation. Chem. Biol., 22(12), 1643-1652, 2015
  14. Xin, X., Akasaka-Manya, K., #Manya, H., Furukawa, J., Kuwabara, N., Okada, K., Tsumoto, H., Higashi, N., Kato, R., Shinohara, Y., Irimura, T., #Endo, T. : POMGNT1 Is Glycosylated by Mucin-Type O-Glycans. Biol. Pharm. Bull., 38(9), 1389-1394, 2015 (#co-corresponding authors)
  15. Manya, H., Endo T. : O-Mannosyl glycan and muscular dystrophy. Sugar chains (Suzuki, T., Ohtsubo, K., Taniguchi, N.), Springer, 235-238, 2015.
  16. Kizuka, Y., Kitazume, S., Fujinawa, R., Saito, T., Iwata, N., Saido, T.C., Nakano, M., Yamaguchi, Y., Hashimoto, Y., Staufenbiel, M., Hatsuta, H., Murayama, S., Manya, H., Endo, T., Taniguchi, N. : An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease. EMBO Mol. Med., 7, 175-189, 2015.
  17. Yaji, S., Manya, H., Nakagawa, N., Takematsu, H., Endo, T., Kannagi, R., Yoshihara, T., Asano, M., Oka, S. : Major glycan structure underlying expression of the Lewis X epitope in the developing brain is O-mannose-linked glycans on phosphacan/RPTPβ. Glycobiology, 25, 376-385, 2015.
  18. Manya, H., Endo T.: Protein O-linked-mannose β-1,2-N-acetyl glucosaminyltransferase 1 (POMGNT1). Handbook of Glycosyl transferases and related genes. (Taniguchi N., Honke K., Fukuda M., Narimatsu H., Yamaguchi Y., Angata T.), Springer, 409-414, 2014
  19. Manya, H., Endo T.: Protein O-mannosyl-transferase 1,2 (POMT1,2). Handbook of Glycosyltransferases and related genes. (Taniguchi N., Honke K., Fukuda M., Narimatsu H., Yamaguchi Y., Angata T.), Springer, 173-179, 2014
  20. Akasaka-Manya, K., Manya, H., Kizuka, Y., Oka, S., Endo, T. : α-Klotho mice demonstrate increased expression of the non-sulfated N-glycan form of the HNK-1 glyco-epitope in kidney tissue. J. Biochem., 156, 107-113, 2014.
  21. Tamaru, Y., Avşar-Ban, E., Manya, H., Endo, T., Akiyama, S. : Molecular characterization of protein O-linked mannose β-1,2-N-acetylglucosaminyltransferase 1 in Zebrafish. J. Glycomics Lipidomics, 4, 111, 2014.
  22. Morise, J., Kizuka, Y., Yabuno, K., Tonoyama, Y., Hashii, N., Kawasaki, N., Manya, H., Miyagoe-Suzuki, Y., Takeda, S., Endo, T., Maeda, N., Takematsu, H., Oka, S.: Structural and biochemical characterization of O-mannose-linked human natural killer-1 glycan expressed on phosphacan in developing mouse brains. Glycobiology, 24, 314-324, 2014.
  23. Jiao, H., Manya, H., Wang, S., Zhang, Y., Li, X., Xiao, J., Yang, Y., Kobayashi, K., Toda, T., Endo, T., Wu, X., Xiong, H. : Novel POMGnT1 mutations cause muscle-eye-brain disease in Chinese patients. Mol. Genet. Genomics., 288, 297-308, 2013.
  24. Ogawa, M., Nakayam, Y., Nakamura, N., Kurosaka, K., Manya, H., Kanagawa, M., Endo, T., Furukawa, K., Okajima, T. : GTDC2 modifies O-mannosylated α-dystroglycan in the endoplasmic reticulum to generate N-acetyl-glucosamine epitopes reactive with CTD110.6 antibody. Biochem. Biophys. Res. Commun., 440, 88-93, 2013.
  25. Avşar-Ban, E., Ishikawa. H., Akiyama, S., Manya, H., Endo, T., Tamaru, T. Functional and heterologous expression of human protein O-linked mannose β-1,2-N-acetylglucosaminyltransferase 1 in zebrafish. J. Biosci. Bioengineer., 114, 237-239, 2012
  26. Nakagawa, N., Manya, H., Toda, T., Endo, T., Oka, S. Human natural killer-1 sulfotransferase (HNK-1ST)-induced sulfate-transfer regulates laminin-binding glycans on α-dystroglycan. J. Biol. Chem., 287, 30823-30832, 2012
  27. Kuga, A., Kanagawa, M., Sudo, A., Chan, Y. M., Tajiri, M., Manya, H., Kikkawa, Y., Nomizu, M., Kobayashi, K., Endo, T., Qi, L. Lu, Wada, Y., and Toda, T. Absence of post-phosphoryl modification in dystroglycanopathy mouse models and wild-type tissues expressing a non-laminin binding form of α-dystroglycan. J. Biol. Chem., 287, 9560-9567, 2012.
  28. Manya, H : Biosynthetic pathway of O-mannosyl glycan in mammals. Trends Glycosci. Glycotech., 23, 272-283, 2011.
  29. Akasaka-Manya, K., Manya, H., Hayashi, M., and Endo, T. Different roles of the two components of human protein O-mannosyltransferase, POMT1 and POMT2. Biochem. Biophys. Res. Commun., 411, 721-725, 2011.
  30. Akasaka-Manya, K., Manya, H., Mizuno, M., Inazu, T., and Endo, T. Effects of length and amino acid sequence of O-mannosyl peptides on substrate specificity of protein O-linked mannose β1,2-N-acetylglucosaminyltransferase 1 (POMGnT1). Biochem. Biophys. Res. Commun., 410, 632-636, 2011.
  31. St.-Pierre, C., Manya, H., Ouellet, M., Clark, G. F., Endo, T., Tremblay, M. J., Sato, S. : Host-soluble Galectin 1 promotes HIV-1 replication through a direct interaction with glycans of viral gp120 and host CD4. J. Virol., 85, 11742-11751, 2011.
  32. Manya, H., Akasaka-Manya, K., Nakajima, A., Kawakita, M., and Endo, T. Role of N-glycans in maintaining the activity of protein O-mannosyltransferases POMT1 and POMT2. J. Biochem., 147, 337-344, 2010.
  33. Manya, H., Akasaka-Manya, K., and Endo, T. Klotho protein deficiency and aging. Geriatr. Gerontol. Int., 10(Suppl. 1), S80-S87, 2010.
  34. Akasaka-Manya, K., Manya, H., Sakurai, Y., Wojczyk, B.S., Kozutsumi, Y., Saito, Y., Taniguchi, N., Murayama, S., Spitalnik, S.L., and Endo, T. Protective effect of N-glycan bisecting GlcNAc residues on β-amyloid production in Alzheimer's disease. Glycobiology, 20, 99-106, 2010.
  35. Akasaka-Manya, K., Manya, H., Sakurai, Y., Wojczyk, B.S., Spitalnik, S.L., and Endo, T. Increased bisecting and core fucosylated N-glycans on mutant human amyloid precursor proteins. Glycoconjugate J., 25, 775-786, 2008.
  36. Manya, H., Chiba, A., Yoshida, A., Wang, X., Chiba, Y., Jigami, Y., Margolis, R. U. and Endo, T.: Demonstration of mammalian protein O-mannosyltransferase activity: Coexpression of POMT1 and POMT2 required for enzymatic activity. Proc. Natl. Acad. Sci. USA, 101(2), 500-505, 2004.
  37. Manya, H., Inomata. M., Fujimori, T., Dohmae, N., Sato, Y., Takio, K., Nabeshima, Y., Endo, T.: Klotho protein deficiency leads to overactivation of µ-calpain. J. Biol. Chem., 277(38), 35503-35508, 2002.
  38. Yoshida, A., Kobayashi, K., Manya, H., Taniguchi, K., Kano, H., Mizuno, M., Inazu, T., Mitsuhashi, H., Takahashi, S., Takeuchi, M., Herrmann, R., Straub, V., Talim, B., Voit, T., Topaloglu, H., Toda, T. and Endo, T.: Muscular Dystrophy and Neuronal Migration Disorder Caused by Mutations in a Glycosyltransferase, POMGnT1. Dev. Cell, 1(5), 717-724, 2001.

【和文】

  1. 萬谷博, 遠藤玉夫, 哺乳類におけるリビトールリン酸含有糖鎖の発見とO-マンノース型糖鎖の生合成機構の解明, 生化学, 2017, 89, 605-612
  2. 桑原直之, 加藤龍一, 萬谷博, 遠藤玉夫, POMGnT1の構造解析による筋ジストロフィー疾患発症機序解明, 日本結晶学会誌, 2017, 59,114-120
  3. 萬谷博: 研究トピックス「先天性筋ジストロフィー症と網膜色素変性症の原因遺伝子の発見」.研究所NEWS, 東京都健康長寿医療センター, 275, 4, 2016.7
    (研究所NEWS:http://www.tmghig.jp/research/publication/news/pdf/rj_no275.pdf
  4. 萬谷博: 抗老化タンパク質とミネラルバランス. 百歳万歳Gabin, エヌシィシィ, 38(3), 34-35, 2016
  5. 萬谷博、遠藤玉夫 今日の話題O-マンノース型糖鎖異常による筋ジストロフィー症 糖鎖分析技術の高感度化がもたらす糖鎖研究の新たな展開. 化学と生物, 51, 702-704, 2013
  6. 赤阪-萬谷啓子、萬谷博、遠藤玉夫: 老化研究の進歩 α-klothoと老化・腎. Geriatric Medicine, 51(6), 619-622, 2013
  7. 萬谷博、遠藤玉夫 最前線 糖鎖異常による筋ジストロフィー症研究の新たな展開. ファルマシア, 48, 718-732, 2012
  8. 萬谷博, 赤阪-萬谷啓子, 遠藤玉夫 klothoマウスを用いた抗老化研究. 薬学雑誌, 130(1), 3-9, 2010
  9. 石神昭人, 萬谷博 老化モデル動物を用いた抗老化研究へのアプローチ. 薬学雑誌, 130, 1-2, 2010
  10. 萬谷博、遠藤玉夫 哺乳類O-マンノース型糖鎖の生合成機構. 糖鎖情報の独自性と普遍性. 蛋白質・核酸・酵素9月号増刊, 53(12), 1429-1433, 2008
  11. 萬谷博 Klothoマウス. 老化・老年病研究のための動物実験ガイドブック, アドスリー, 101-107, 2008