Enzymatic remodeling of heparan sulfate: a therapeutic strategy for systemic amyloidoses

• Project/Area Number: 17K16123
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: Wakayama Medical University (2018); The University of Tokushima (2017)
• Principal Investigator: Kazuchika Nishitsuji 和歌山県立医科大学, 医学部, 講師 (40532768)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: アミロイド / アミロイドーシス / ヘパラン硫酸 / グリコサミノグリカン / 細胞外糖鎖 / トランスサイレチン / 細胞外硫酸化糖鎖

Outline of Final Research Achievements

The highly sulfated domains of heparan sulfate (HS), also known as HS S-domains, concsist of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Here, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis. In in vitro assays, heparin, a structural analog of HS S-domains, promoted aggregation of transthyretin in an HS S-domain-dependent manner. Interactions of cells with transthyretin fibrils and cytotoxicity of these fibrils depended on HS S-domains. Glypican-5, encoded by the susceptibility gene for nephrotic syndrome GPC5, was found to be accumulated in the transthyretin amyloidosis kidney. Thus, we propose that HS S-domains can be a novel therapeutic targets of transthyretin amyloidosis.

Academic Significance and Societal Importance of the Research Achievements

ATTRアミロイドーシスは日本国内にも患者の集積地が存在する難治性の疾患である。本失火には肝移植の有効性が確立されてはいるが、ドナー不足、患者やドナーに対する精神・肉体的な負担、移植後のアミロイドーシス進行といった問題、病気の進行や年齢等の理由により約8割の患者は移植手術の適用とならない。従ってより一般的かつ侵襲性の低い新たな治療方法の開発が必要である。本研究により、ヘパラン硫酸多硫酸化ドメインがTTR線維の形成や細胞毒性の発揮に重要であることが分かり、ヘパラン硫酸多硫酸化ドメインを選択的に酵素分解することによりATTRアミロイドーシス病態を制御する新たな治療戦略が示唆された。

Research Products

• [Int'l Joint Research] Academia Sinica(その他の国・地域 Taiwan)
• [Int'l Joint Research] Universite de Lille 1(フランス)
• [Journal Article] A novel amphipathic cell-penetrating peptide based on the N-terminal glycosaminoglycan binding region of human apolipoprotein E (2019)
  • Author(s): Ohgita Takashi、Takechi-Haraya Yuki、Nadai Ryo、Kotani Mana、Tamura Yuki、Nishikiori Karin、Nishitsuji Kazuchika、Uchimura Kenji、Hasegawa Koki、Sakai-Kato Kumiko、Akaji Kenichi、Saito Hiroyuki
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Biomembranes Volume: 1861 Issue: 3 Pages: 541-549
  • DOI: 10.1016/j.bbamem.2018.12.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity (2019)
  • Author(s): Kameyama H, Uchimura K, Yamashita T, Kuwabara K, Mizuguchi M, Hung SC, Okuhira K, Masuda T, Kosugi T, Ohgita T, Saito H, Ando Y, Nishitsuji K.
  • Journal Title: The American Journal of Pathology Volume: 189 Issue: 2 Pages: 308-319
  • DOI: 10.1016/j.ajpath.2018.09.015
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effect of Phosphatidylserine and Cholesterol on Membrane-mediated Fibril Formation by the N-terminal Amyloidogenic Fragment of Apolipoprotein A-I (2018)
  • Author(s): Mizuguchi Chiharu、Nakamura Mitsuki、Kurimitsu Naoko、Ohgita Takashi、Nishitsuji Kazuchika、Baba Teruhiko、Shigenaga Akira、Shimanouchi Toshinori、Okuhira Keiichiro、Otaka Akira、Saito Hiroyuki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5497-5497
  • DOI: 10.1038/s41598-018-23920-3
  • Peer Reviewed / Open Access
• [Journal Article] Heparan sulfate S-domains and extracellular sulfatases (Sulfs): their possible roles in protein aggregation diseases (2018)
  • Author(s): Nishitsuji, K.
  • Journal Title: Glycoconjugate Journal Volume: 35 Issue: 4 Pages: 387-396
  • DOI: 10.1007/s10719-018-9833-8
  • Peer Reviewed
• [Journal Article] Effect of coffee or coffee components on gut microbiome and short-chain fatty acids in a mouse model of metabolic syndrome (2018)
  • Author(s): Nishitsuji Kazuchika、Watanabe Syunsuke、Xiao Jinzhong、Nagatomo Ryosuke、Ogawa Hirohisa、Tsunematsu Takaaki、Umemoto Hitomi、Morimoto Yuki、Akatsu Hiroyasu、Inoue Koichi、Tsuneyama Koichi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 16173-16173
  • DOI: 10.1038/s41598-018-34571-9
  • NAID: 120006842036
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of the gut microbiome and plasma short-chain fatty acid profiles in a spontaneous mouse model of metabolic syndrome. (2017)
  • Author(s): Analysis of the gut microbiome and plasma short-chain fatty acid profiles in a spontaneous mouse model of metabolic syndrome.
  • Journal Title: Sci Rep. Volume: 7(1) Issue: 1 Pages: 15876-15876
  • DOI: 10.1038/s41598-017-16189-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immunochemical Approach for Monitoring of Structural Transition of ApoA-I upon HDL Formation Using Novel Monoclonal Antibodies (2017)
  • Author(s): H. Kimura, S. Mikawa, C. Mizuguchi, Y. Horie, I. Morita, H. Oyama, T. Ohgita, K. Nishitsuji, A. Takeuchi, S. Lund-Katz, K. Akaji, N. Kobayashi, H. Saito
  • Journal Title: Sci. Rep. Volume: 7 Issue: 1 Pages: 2988-2988
  • DOI: 10.1038/s41598-017-03208-8
  • NAID: 120006534990
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer's pathology. (2017)
  • Author(s): Zhang Z, Takeda-Uchimura Y, Foyez T, Ohtake-Niimi S, Narentuya, Akatsu H, Nishitsuji K, Michikawa M, Wyss-Coray T, Kadomatsu K, Uchimura K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 114(14) Issue: 14 Pages: 114-114
  • DOI: 10.1073/pnas.1615036114
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Animal models for analyzing metabolic syndrome-associated liver diseases (2017)
  • Author(s): Tsuneyama Koichi、Nishitsuji Kazuchika、Matsumoto Minoru、Kobayashi Tomoko、Morimoto Yuki、Tsunematsu Takaaki、Ogawa Hirohisa
  • Journal Title: Pathology International Volume: 67 Issue: 11 Pages: 539-546
  • DOI: 10.1111/pin.12600
  • Peer Reviewed
• [Journal Article] Sulfated glycosaminoglycans in protein aggregation diseases (2017)
  • Author(s): Nishitsuji Kazuchika、Uchimura Kenji
  • Journal Title: Glycoconjugate Journal Volume: 34 Issue: 4 Pages: 453-466
  • DOI: 10.1007/s10719-017-9769-4
  • Peer Reviewed
• [Presentation] Pathological roles of heparan sulfate S-domains in ATTR amyloidosis (2018)
  • Author(s): Kazuchika Nishitsuji, Kenji Uchimura, Taro Yamashita, Kaori Kuwabara, Hirokazu Kameyama, Mineyuki Mizuguchi, Keiichiro Okuhira, Takashi Ohgita, Hiroyuki Saito, Yukio Ando
  • Organizer: XVIth International Symposium on Amyloidosis
  • Int'l Joint Research
• [Presentation] HS S-domains that accumulate in ATTR amyloidosis patients accelerate and mediate formation and cytotoxicity of transthyretin fibrils (2018)
  • Author(s): Kazuchika Nishitsuji, Kenji Uchimura, Taro Yamashita, Hirokazu Kameyama, Kaori Kuwabara, Mineyuki Mizuguchi, Shang-Cheng Hung, Keiichiro Okuhira, Takashi Ohgita, Hiroyuki Saito, Yukio Ando
  • Organizer: 2018 ANNUAL MEETING OF THE SOCIETY FOR GLYCOBIOLOGY
  • Int'l Joint Research
• [Presentation] Gut dysbiosis and altered plasma short chain fatty acid profile underlie the pathogenesis of nonalcoholic steatohepatitis. (2017)
  • Author(s): Nishitsuji K., Inoue K., Akatsu H., Tsuneyama, K.
  • Organizer: The Liver Meeting 2017 (Walter E. Washington Convention Center, Washington DC)
  • Int'l Joint Research
• [Presentation] Glycosaminoglycans in protein aggregation diseases. (2017)
  • Author(s): Nishitsuji K.
  • Organizer: 1st International Conference on the Glycobiology of Nervous System, (Korea University, Seoul, Korea)
  • Int'l Joint Research / Invited
• [Presentation] ATTRアミロイドーシスにおけるヘパラン硫酸多硫酸化ドメイン(S-ドメイン)の役割の解明 (2017)
  • Author(s): 亀山泰和、内村健治、山下太郎、水口峰之、坂下直実、斎藤博幸、奥平桂一郎、安東由喜雄、西辻和親
  • Organizer: 第5回日本アミロイドーシス研究会学術集会 京都
• [Presentation] ATTRアミロイドーシスにおけるヘパラン硫酸多硫酸化ドメインの役割の解明 (2017)
  • Author(s): 亀山泰和、内村健治、山下太郎、水口峰之、坂下直実、斎藤博幸、奥平桂一郎、安東由喜雄、西辻和親
  • Organizer: 膜シンポジウム2017 富山