Elucidation of the molecular mechanism underlying TTR monomer unfolding and aggregate formation and its application to therapeutic approaches for FAP
| Project/Area Number |
18K06659
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
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| Research Institution | Kumamoto University |
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Principal Investigator |
Sato Takashi 熊本大学, 大学院生命科学研究部(薬), 助教 (70555755)
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| Co-Investigator(Kenkyū-buntansha) |
森岡 弘志 熊本大学, 大学院生命科学研究部(薬), 教授 (20230097)
小橋川 敬博 熊本大学, 大学院生命科学研究部(薬), 准教授 (90455600)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | トランスサイレチン / アミロイドーシス / ジスルフィド結合 |
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| Outline of Final Research Achievements |
Transthyretin (TTR), a serum protein, is responsible for senile and hereditary amyloidosis. TTR forms amyloid fibrils by dissociating the tetramer into a monomer, denaturation of the monomer, leading to aggregate formation. In this study, we aimed to clarify how the structure of the TTR monomer is denatured by genetic mutations and how the denatured monomers form cytotoxic aggregates. We found that TTR aggregates forming intermediates with disulfide bonds between molecules via free cysteine residues upon denaturation. Furthermore, our results suggest that this intermediate is cytotoxic itself. This study allowed us to propose a new mechanism of amyloid formation in TTR.
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| Academic Significance and Societal Importance of the Research Achievements |
従来の研究で汎用されていた酸性条件による変性とは異なり、本研究ではより生理的環境に近い中性条件におけるTTRのアミロイド形成機構を解析した。変性条件を緩和させることで不安定な中間体構造の同定につながり、細胞毒性を示す凝集体を特定できた点に本研究の学術的意義がある。細胞毒性を示す凝集体形成にはTTR分子間のジスルフィド結合が必須であることから、加齢に伴う酸化還元バランスの破綻が疾患発症に関与することを示唆された。本研究は疾患発症概念や予防薬開発において酸化還元バランスの重要性を提起する点で社会的意義がある。
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Report
(4 results)
Research Products
(13 results)
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[Journal Article] Characterization of Non-amyloidogenic G101S Transthyretin2018
Author(s)
Yuriko Wakita, Takashi Sato, Keisuke Chosa, Mary Ann Suico, Ryoko Sasaki, Shingo Kawano, Nami Hashimoto, Yuriko Teranishi, Yoshiki Imai, Hiroshi Morioka, Tsuyoshi Shuto, Hirofumi Kai
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Journal Title
Biological and Pharmaceutical Bulletin
Volume: 41
Issue: 4
Pages: 628-636
DOI
NAID
ISSN
0918-6158, 1347-5215
Related Report
Peer Reviewed / Open Access
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