Molecular Glycobiology

Theme Leader :
Hiroshi Manya, Ph.D.
Researcher :
Keiko Akasaka, Ph.D., Rieko Imae, Ph.D., Shunsuke Hoshino, Ph.D.

Post-genomic research, Sugar chain, Neuro-muscular function, Aging model mouse, Alzheimer's disease

1. 1.Dementia-associated changes of glycoproteins.
2. 2.Research on a mouse model resembling human aging
3. 3.Glycobiology on neuro-muscular functions

We are mainly focusing on post-genomic research in aging. We try to elucidate the mechanisms of normal aging and geriatric diseases by analyses of the processes of posttranslational modifications, specially focusing on glycosylation.

1. 1. Dementia-associated change of glycoproteins
   Glycosylation is a common type of posttranslational modification of proteins that can affect its function in many ways. We are focusing on changes of the glycosylation state of brain glycoproteins during dementia.
2. 2. Research on a mouse model resembling human aging
   Using an animal model, klotho mouse, that prematurely shows phenotypes resembling human aging, we found the abnormal activation of calpain. We try to characterize these detailed processes.
3. 3. Glycobiology on neuro-muscular functions
   We have found O-mannosyl glycan which plays an essential role in muscle function and maintenance. Defects in O-mannosyl glycan are the primary cause of congenital muscular dystrophies. We also revealed the synthetic pathway and entire structure of O-mannosyl glycan, including ribitol-5-phosphate, which is a novel structure in mammals. Thus, glycans are important for muscle function, we are trying to unravel the relationship of the glycan changes and age-associated deterioration of muscle.



Based on above strategies, we will open a new venue for the post-genomic research in gerontology and geriatrics.

1. 1. Manya, H., Kuwabara, N., Kato, R., Endo, T.: FAM3B/PANDER-like carbohydrate-binding domain in a glycosyltransferase, POMGNT1. Methods Mol. Biol., 2132, 609-619, 2020
2. 2. Akasaka-Manya, K., Manya, H.: The role of APP O-glycosylation in Alzheimer's disease. Biomolecules, 10(11),1569, 2020
3. 3. Imae, R., Kuwabara, N., Manya, H., Kato, R., Endo, T.: Biosynthetic mechanisms of a unique ribitol phosphate-containing glycan by FKRP, a ribitol phosphate transferase. Trends Glycosci. Glycotech., 32(190), E195-E200, 2020
4. 4. Furukawa, J-I., Hanamatsu, H., Nishikaze, T., Manya, H., Miura, N., Yagi, H., Yokota, I., Akasaka-Manya, K., Endo, T., Kanagawa, M., Iwasaki, N., Tanaka, K.: Lactone-driven ester-to-amide derivatization for sialic acid linkage-specific alkylamidation. Anal Chem., 92(21), 14383-14392, 2020
5. 5. Akasaka-Manya, K., #Manya, H., Nadanaka, S., Kitagawa, H., Kondo, Y., Ishigami, A., #Endo, T.: Decreased ADAM17 expression in the lungs of α-Klotho reduced mouse. J. Biochem., 167(5),483-493, 2020 (#co-senior authors)
6. 6. *Kuwabara, N., *Imae, R., Manya, H., Tanaka, T., Mizuno, M., Tsumoto, H., Kanagawa, M., Kobayashi, K., Toda, T., Senda, T., #Endo, T., #Kato, R.: Crystal structures of fukutin-related protein (FKRP), a ribitol-phosphate transferase related to muscular dystrophy. Nat. Commun., 11(1), 303, 2020 (*co-first authors, #co-senior authors)
7. 7. Imae, R., Manya, H., Tsumoto, H., Osumi, K., Tanaka, T., Mizuno, M., Kanagawa, M., Kobayashi, K., Toda, T., Endo, T: CDP-glycerol inhibits the synthesis of the functional O-mannosyl glycan of α-dystroglycan. J. Biol. Chem., 293(31), 12186-12198, 2018
8. 8. Manya, H., Mechanisms of O-mannosyl glycan biosynthesis in mammals. Trends in Glycosci. Glycotech., 31(181), SE63 - SE64, 2019
9. 9. 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
10. 10. 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
11. 11. Kanagawa, M., Manya, H.: Tatsushi Toda and Tamao Endo win 107th Japan Academy Prize. Glycobiology, 27(7), 599-600, 2017
12. 12. Yamashita, K. et al.: Experimental phase determination with selenomethionine or mercury-derivatization in serial femtosecond crystallography. IUCrJ, 4, 639-647, 2017
13. 13. 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
14. 14. 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)
15. 15. 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
16. 16. 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 α-dystroglycan. Proc. Natl. Acad. Sci. USA, 113 (33), 9280-9285, 2016 (#co-senior authors)
17. 17. *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)
18. 18. Akasaka-Manya, K., Manya, H., Endo, T.: Function and change with aging of α-klotho in the kidney. Klotho, Vitam. Horm., vol. 101 (Gerald Litwack ed.), Academic Press, pp 239-256, 2016
19. 19. *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)
20. 20. 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)
21. 21. 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
22. 22. 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)
23. 23. Manya, H., Endo T. : O-Mannosyl glycan and muscular dystrophy. Sugar chains (Suzuki, T., Ohtsubo, K., Taniguchi, N.), Springer, 235-238, 2015.
24. 24. 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.
25. 25. 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.
26. 26. 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
27. 27. 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
28. 28. 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.
29. 29. 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.
30. 30. 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.
31. 31. 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.
32. 32. 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.
33. 33. 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
34. 34. 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
35. 35. 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.
36. 36. Manya, H : Biosynthetic pathway of O-mannosyl glycan in mammals. Trends Glycosci. Glycotech., 23, 272-283, 2011.
37. 37. 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.
38. 38. 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.
39. 39. 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.
40. 40. 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.
41. 41. Manya, H., Akasaka-Manya, K., and Endo, T. Klotho protein deficiency and aging. Geriatr. Gerontol. Int., 10(Suppl. 1), S80-S87, 2010.
42. 42. 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.
43. 43. 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.
44. 44. 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.
45. 45. 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.
46. 46. 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.