Role of glycosaminoglycans in ATTR amyloidosis

• Project/Area Number: 15K19488
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Neurology
• Research Institution: The University of Tokushima
• Principal Investigator: NISHITSUJI Kazuchika 徳島大学, 大学院医歯薬学研究部(医学系), 助教 (40532768)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: グリコサミノグリカン / ヘパラン硫酸 / アミロイド / アミロイドーシス / トランスサイレチン

Outline of Final Research Achievements

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is characterized by transthyretin (TTR) deposition in various tissues, including the kidneys. Amyloid depositions in vivo contain protein components and non-protein constituents besides the main protein fibrils. The non-protein constituents include glycosaminoglycans (GAGs), and are thought to be involved in the pathogenesis and pathology of protein aggregation diseases, such as protein aggregation and protein aggregate-induced tissue/organ damages.Here, we showed that heparan sulfate and heparin, members of naturally occuring GAGs, promoted the aggregation of TTR and mediated the cellular interaction of TTR fibrils. Furthermore, heparan sulfate were accumulated in the kidneys of patients having TTR-FAP. Our results will assist in the design of anti-amyloid agents.

Research Products

• [Int'l Joint Research] Acadmica Sinica(Taipei)
• [Journal Article] Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes. (2016)
  • Author(s): Kameyama H., Nakajima H., Nishitsuji K., Mikawa S., Uchimura K., Kobayashi N., Okuhira K., Saito H., and Sakashita N.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 30391-30391
  • DOI: 10.1038/srep30391
  • NAID: 120006534966
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Heparin promotes fibril formation by the N-terminal fragment of amyloidogenic apolipoprotein A-I (2016)
  • Author(s): Mikawa, S., Mizuguchi, C., Nishitsuji, K., Baba, T., Shigenaga,A., Shimanouchi, T., Sakashita, N., Otaka, A., Akaji, K., Saito, H.
  • Journal Title: FEBS Letters Volume: 590(20) Issue: 20 Pages: 3492-3500
  • DOI: 10.1002/1873-3468.12426
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] CUL2-mediated clearance of misfolded TDP-43 is paradoxically affected by VHL in oligodendrocytes in ALS. (2016)
  • Author(s): Uchida T, Tamaki Y, Ayaki T, Shodai A, Kaji S, Morimura T, Banno Y, Nishitsuji K, Sakashita N, Maki T, Yamashita H, Ito H, Takahashi R, Urushitani M.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 19118-19136
  • DOI: 10.1038/srep19118
  • NAID: 120005689210
  • Peer Reviewed / Open Access
• [Journal Article] The polyphenol (-)-epigallocatechin-3-gallate prevents apoA-IIowa amyloidosis in vitro and protects human embryonic kidney 293 cells against amyloid cytotoxicity. (2016)
  • Author(s): Nakajima H, Nishitsuji K, Kawashima H, Kuwabara K, Mikawa S, Uchimura K, Akaji K, Kashiwada Y, Kobayashi N, Saito H, Sakashita N
  • Journal Title: Amyloid Volume: 23 Issue: 1 Pages: 17-25
  • DOI: 10.3109/13506129.2015.1113167
  • Peer Reviewed
• [Journal Article] Enthalpy-driven interactions with sulfated glycosaminoglycans promote cell membrane penetration of arginine peptides. (2016)
  • Author(s): Takechi-Haraya Y, Nadai R, Kimura H, Nishitsuji K, Uchimura K, Sakai-Kato K, Ka-wakami K, Shigenaga A, Kawakami T, Otaka A, Hojo H, Sakashita N, Saito H
  • Journal Title: Biochimica et Biophysica Acta Volume: - Issue: 6 Pages: 1339-1349
  • DOI: 10.1016/j.bbamem.2016.03.021
  • Peer Reviewed
• [Journal Article] C-terminal region of GADD34 regulates eIF2α dephosphorylation and cell proliferation in CHO-K1 cells. (2016)
  • Author(s): Otsuka R, Harada N, Aoki S, Shirai K, Nishitsuji K, Nozaki A, Hatakeyama A, Shono M, Mizusawa N, Yoshimoto K, Nakaya Y, Kitahata H, Sakaue H
  • Journal Title: Cell stress and chaperones Volume: 21 Issue: 1 Pages: 2940-2940
  • DOI: 10.1007/s12192-015-0633-9
  • Peer Reviewed
• [Journal Article] Enzymatic Remodeling of Heparan Sulfate: A Therapeutic Strategy for Systemic and Localized Amyloidoses? (2016)
  • Author(s): Nishitsuji K. Saito H., and Uchimura K.
  • Journal Title: Neur. Regener. Res. Volume: 11 Issue: 3 Pages: 408-409
  • DOI: 10.4103/1673-5374.179043
  • Peer Reviewed / Open Access
• [Journal Article] 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及びSulf の役割 (2016)
  • Author(s): 西辻 和親、内村 健治
  • Journal Title: Medical Science Digest Volume: 42 Pages: 608-612
• [Journal Article] Arachidonic Acid Diet Attenuates Aβ Deposition in Tg2576 Mice. (2015)
  • Author(s): Hosono T, Nishitsuji K, Nakamura T, Jung CG, Kontani M, Tokuda H, Kawashima H, Kiso Y, Suzuki T, Michikawa M
  • Journal Title: Brain Res Volume: 10 Pages: 1613-1629
  • DOI: 10.1016/j.brainres.2015.04.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Arachidonic or docosahexaenoic acid diet prevents memory impairment in Tg2576 mice. (2015)
  • Author(s): Hosono T, Mouri A, Nishitsuji K, Jung CG, Kontani M, Tokuda H, Kawashima H, Shibata H, Suzuki T, Nabeshima T, Michikawa M.
  • Journal Title: J Alzheimers Dis Volume: 48 Issue: 1 Pages: 149-162
  • DOI: 10.3233/jad-150341
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] K604, a specific acyl-CoA:CoA:cholesterol acyltransferase 1 inhibitor, suppresses proliferation of U251-MG glioblastoma cells (2015)
  • Author(s): Ohmoto, Takuji Nishitsuji, Kazuchika Yoshitani, Nobuyuki Mizuguchi, Makoto Yanagisawa, Yuto Saito, Hiroyuki Sakashita, Naomi
  • Journal Title: Molecular Medicine Reports Volume: 12 Issue: 4 Pages: 6037-6042
  • DOI: 10.3892/mmr.2015.4200
  • Peer Reviewed
• [Journal Article] CD44-expressing undifferentiated carcinoma with rhabdoid features of the pancreas: molecular analysis of aggressive invasion and metastasis. (2015)
  • Author(s): Ohtomo T, Yoshitani N, Nishitsuji K, Takayama T, Yagagisawa Y, Takeya M, Sakashita N
  • Journal Title: Pathology International Volume: 65 Issue: 5 Pages: 264-270
  • DOI: 10.1111/pin.12283
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cellular Interaction and Cytotoxicity of the Iowa Mutation of Apolipoprotein A-I (ApoA-IIowa) Amyloid Mediated by Sulfate Moieties of Heparan Sulfate (2015)
  • Author(s): Kuwabara, K., Nishitsuji, K., Uchimura, K., Hung, S.C., Mizuguchi, M., Nakajima, H., Mikawa, S., Kobayashi, N., Saito, H., and Sakashita, N.
  • Journal Title: J Biol Chem Volume: 290 Issue: 40 Pages: 24210-24221
  • DOI: 10.1074/jbc.m115.652545
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Cellular interaction and cytotoxicity of amyloid fibrils of the Iowa mutant of apolipoprotein A-I (apoA-IIowa) are mediated by sulfate moieties of heparan sulfate. (2016)
  • Author(s): Nishitsuji K., Kuwabara K., Uchimura K., Hung SC., Kobayashi N., Saito H., Sakashita N.
  • Organizer: The XVth International Symposium on Amyloidosis
  • Place of Presentation: Uppsala (Sweden)
  • Year and Date: 2016-07-03
  • Int'l Joint Research
• [Presentation] ApoA-I線維はオートファジー/リソソーム系の機能を障害する (2016)
  • Author(s): 亀山泰和、西辻和親、小林典裕、斎藤博幸、坂下直実
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター(宮城県仙台市)
  • Year and Date: 2016-05-12
• [Presentation] G26R変異型アポリポタンパク質A1線維の細胞毒性はリソソーム依存的である (2016)
  • Author(s): 亀山泰和、西辻和親、奥平桂一郎、小林典弘、斎藤博幸、坂下直実
  • Organizer: 第4回日本アミロイドーシス研究会学術集会
  • Place of Presentation: KKRホテル東京(東京都千代田区)
• [Presentation] AApoA-I アミロイドーシスにおけるオートファジー ─ リソソーム系の役割 (2015)
  • Author(s): 亀山 泰和, 西辻 和親, 小林 典裕, 斎藤 博幸, 坂下 直実
  • Organizer: 日本病理学会 第61回秋期特別総会
  • Place of Presentation: 東京大学安田講堂（東京都文京区）
  • Year and Date: 2015-11-15
• [Presentation] AApoAI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 (2015)
  • Author(s): 桑原香織、西辻和親、山下太郎、小林典裕、内村健治、安東由喜雄、斎藤博幸、坂下直実
  • Organizer: 日本アミロイドーシス研究会第3回学術集会
  • Place of Presentation: KKRホテル東京（東京都千代田区）
  • Year and Date: 2015-08-20
• [Presentation] ApoA-Iアミロイドの毒性に対するヘパラン硫酸糖鎖の影響 (2015)
  • Author(s): 西辻和親、桑原香織、小林典裕、内村健治、坂下直実、斎藤博幸
  • Organizer: 日本膜学会第37年会
  • Place of Presentation: 早稲田大学（東京都新宿区）
  • Year and Date: 2015-05-14
• [Presentation] apoA1アミロイドの毒性に対するヘパラン硫酸糖鎖の影響 (2015)
  • Author(s): 桑原香織、西辻和親、小林典裕、内村健治、斎藤博幸、坂下直実
  • Organizer: 第104回 日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-30