Elucidation of structure, modification mechanism, pathophysiological roles of a novel posttranslational modification, post-phosphoryl sugar chain

• Project/Area Number: 15H04352
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Kobe University
• Principal Investigator: Kanagawa Motoi 神戸大学, 医学研究科, 講師 (00448044)
• Co-Investigator(Kenkyū-buntansha): 片野坂 友紀 岡山大学, 医歯薬学総合研究科, 助教 (60432639) ; 山口 芳樹 国立研究開発法人理化学研究所, 主任研究員研究室等, チームリーダー (90323451) ; 永森 收志 大阪大学, 医学系研究科, 准教授 (90467572)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
• Keywords: 糖鎖 / 筋ジストロフィー / リビトールリン酸 / フクチン / 細胞・組織 / 糖鎖生物学 / ジストログリカン

Outline of Final Research Achievements

Post-phosphoryl sugar chain is associated with muscular dystrophy and brain malformation and thus is believed to play important physiological roles. However, its structure, modification mechanism, and physiological functions are remained to be elucidated. In this study, we identified tandemly connected ribitol-phosphate, a novel post-modification unit in mammals, as a substance of post-phosphoryl modification. We also identified four enzymes involved in the biosynthesis of ribitol-phosphate modification. These enzymes are encoded by genes responsible for muscular dystrophy. Furthermore, we generated model mice for ribitol-phosphate deficiency and revealed pathomechamism of brain abnormality in muscular dystrophy patients, leading to a proposal of novel therapeutic strategies.

Research Products

• [Journal Article] Cell endogenous activities of fukutin and FKRP coexist with the ribitol xylosyltransferase, TMEM5. (2018)
  • Author(s): Nishihara, R., Kobayashi, K., Imae, R., Tsumoto, H., Manya, H., Mizuno, M., Kanagawa, M., Endo, T., and Toda, T.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 497 Issue: 4 Pages: 1025-1030
  • DOI: 10.1016/j.bbrc.2018.02.162
  • Peer Reviewed / Open Access
• [Journal Article] Ribitol-phosphate-a newly identified posttranslational glycosylation unit in mammals: structure, modification enzymes and relationship to human diseases (2018)
  • Author(s): Kanagawa Motoi、Toda Tatsushi
  • Journal Title: The Journal of Biochemistry Volume: 163 Issue: 5 Pages: 359-369
  • DOI: 10.1093/jb/mvy020
  • Peer Reviewed / Open Access
• [Journal Article] Temporal requirement of dystroglycan glycosylation during brain development and rescue of severe cortical dysplasia via gene delivery in the fetal stage (2018)
  • Author(s): Sudo Atsushi、Kanagawa Motoi、Kondo Mai、Ito Chiyomi、Kobayashi Kazuhiro、Endo Mitsuharu、Minami Yasuhiro、Aiba Atsu、Toda Tatsushi
  • Journal Title: Human molecular genetics Volume: 27 Issue: 7 Pages: 1174-1185
  • DOI: 10.1093/hmg/ddy032
  • NAID: 120006459805
  • Peer Reviewed / Open Access
• [Journal Article] Muscular Dystrophy with Ribitol-Phosphate Deficiency: A Novel Post-Translational Mechanism in Dystroglycanopathy (2017)
  • Author(s): Kanagawa Motoi、Toda Tatsushi
  • Journal Title: Journal of Neuromuscular Diseases Volume: 4 Issue: 4 Pages: 259-267
  • DOI: 10.3233/jnd-170255
  • NAID: 120006811130
  • Peer Reviewed / Open Access
• [Journal Article] The Ror1 receptor tyrosine kinase plays a critical role in regulating satellite cell proliferation during regeneration of injured muscle (2017)
  • Author(s): Kamizaki Koki、Doi Ryosuke、Hayashi Makoto、Saji Takeshi、Kanagawa Motoi、Toda Tatsushi、Fukada So-ichiro、Ho Hsin-Yi Henry、Greenberg Michael Eldon、Endo Mitsuharu、Minami Yasuhiro
  • Journal Title: Journal of Biological Chemistry Volume: 292 Issue: 38 Pages: 15939-15951
  • DOI: 10.1074/jbc.m117.785709
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The muscular dystrophy gene TMEM5encodes a ribitol β1-4 Xylosyltransferase required for the functional glycosylation of dystroglycan. (2016)
  • Author(s): Manya, H., Yamaguchi, Y., Kanagawa, M., Kobayashi, K., Tajiri, M., Akasaka-Manya, K., Kawakami, H., Mizuno, M., Wada, Y., Toda, T., and Endo, T.
  • Journal Title: J. Biol. Chem Volume: 291 Issue: 47 Pages: 24618-24627
  • DOI: 10.1074/jbc.m116.751917
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of α-dystroglycan. (2016)
  • Author(s): Kuwabara N, Manya H, Yamada T, Tateno H, Kanagawa M, Kobayashi K, Akasaka-Manya K, Hirose Y, Mizuno M, Ikeguchi M, Toda T, Hirabayashi J, Senda T, Endo T, Kato R.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 113 Issue: 33 Pages: 9280-9285
  • DOI: 10.1073/pnas.1525545113
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy (2016)
  • Author(s): 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.
  • Journal Title: Cell Reports Volume: 14 Issue: 9 Pages: 2209-2223
  • DOI: 10.1016/j.celrep.2016.02.017
  • NAID: 120005728438
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy: Roles of ISPD, fukutin, and FKRP in α-dystroglycan glycosylation (2017)
  • Author(s): Motoi Kanagawa, Kazuhiro Kobayashi, Michiko Tajiri, Hiroshi Manya, Atsushi Kuga, Yoshiki Yamaguchi, Yoshinao Wada, Tamao Endo, Tatsushi Toda
  • Organizer: Experimental Biology 2017
  • Int'l Joint Research
• [Presentation] 筋ジストロフィー発症に関わる糖鎖構造の解明と修飾酵素の同定 (2017)
  • Author(s): 金川基
  • Organizer: 生命科学系学会合同年次大会
  • Invited
• [Presentation] Mechanobiology of Muscle and Sugar Chain (2017)
  • Author(s): Motoi Kanagawa
  • Organizer: The 3rd International Symposium on Mechanobiology
  • Int'l Joint Research / Invited
• [Presentation] 新型の翻訳後修飾体「リビトールリン酸」の同定～修飾機序と筋ジストロフィー病態への関与～ (2016)
  • Author(s): 金川 基、小林 千浩、田尻 道子、萬谷 博、久我 敦、山口 芳樹、和田 芳直、遠藤 玉夫、戸田 達史
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
  • Invited
• [Presentation] Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy: Roles of ISPD, fukutin, and FKRP in alpha-dystroglycan glycosylation (2016)
  • Author(s): Kanagawa, M., Kobayashi K., Tajiri M., Manya H., Kuga A., Yamaguchi Y., Wada Y., Endo T., Toda T.
  • Organizer: New Directions in Biology and Disease of Skeletal Muscle Conference
  • Place of Presentation: オーランド
  • Year and Date: 2016-06-29
  • Int'l Joint Research
• [Presentation] 新規糖鎖ユニット“リビトールリン酸”の同定と筋ジストロフィーへの関与 (2016)
  • Author(s): 金川 基、小林 千浩、田尻 道子、萬谷 博、久我 敦、山口 芳樹、和田 芳直、遠藤 玉夫、戸田 達史
  • Organizer: 第63回日本生化学会近畿支部例会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-31
• [Presentation] 新型の翻訳後修飾ユニット“リビトールリン酸” と筋ジストロフィー (2016)
  • Author(s): 金川 基
  • Organizer: 関西グライコフォーラム
  • Place of Presentation: 大阪
  • Year and Date: 2016-05-14
  • Invited
• [Presentation] Pathological roles of abnormal glycosylation of dystroglycan in congenital muscular dystrophy with brain anomaly (2016)
  • Author(s): 金川 基
  • Organizer: The 3rd International Symposium on Glyco-Neuroscience
  • Place of Presentation: 淡路
  • Year and Date: 2016-01-14
  • Int'l Joint Research
• [Presentation] 糖鎖修飾異常型筋ジストロフィーの病態機序と治療戦略 (2015)
  • Author(s): 金川 基、戸田 達史
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学会年会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] 糖鎖異常型筋ジストロフィーモデルに対する遺伝子治療 (2015)
  • Author(s): 金川 基、大塚 喜久、小林 千浩、千代 智子、岡田 尚巳、武田 伸一、戸田 達史
  • Organizer: 第１回日本筋学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-08-08
• [Presentation] 糖転移酵素LARGE活性を応用したジストログリカノパチー治療の検討 (2015)
  • Author(s): 大塚 喜久、金川 基、千代 智子、小林 千浩、岡田 尚巳、武田 伸一、戸田 達史
  • Organizer: 第34回日本糖質学会年会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-31
• [Remarks] 神戸大学医学研究科分子脳科学
  • URL: http://www.med.kobe-u.ac.jp/clgene/
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/clgene/
• [Patent(Industrial Property Rights)] ジストログリカン糖鎖修飾異常に伴う疾患の治療剤 (2016)
  • Inventor(s): 戸田 達史、小林 千浩、金川 基、他
  • Industrial Property Rights Holder: 国立大学法人神戸大学、他
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-160390
  • Filing Date: 2016-08-18