Investigation of the pathogenesis and diagnostic method of age-related EFEMP1 amyloidosis

• Project/Area Number: 17K08987
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kumamoto University
• Principal Investigator: Tasaki Masayoshi 熊本大学, 大学院生命科学研究部(保), 助教 (50613402)
• Co-Investigator(Kenkyū-buntansha): 安東 由喜雄 熊本大学, 大学院生命科学研究部(医), 教授 (20253742) ; 大林 光念 熊本大学, 大学院生命科学研究部(保), 教授 (90361899) ; 山下 太郎 熊本大学, 病院, 非常勤診療医師 (90381003)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: アミロイドーシス / アミロイド / 老化 / EFEMP1 / 静脈 / 質量分析

Outline of Final Research Achievements

Amyloidosis is a group of disorders characterized by the deposition of amyloid fibrils in extracellular space. We newly identified EGF-containing fibulin-like extracellular matrix protein 1（EFEMP1）as a novel amyloid precursor protein. However, the pathogenesis is not fully understood. In this study, we investigated the pathogenesis of novel EFEMP1 amyloidosis. Our study revealed the following findings. 1) The occurrence and amount of EFEMP1 amyloid increased with age in GI tract, lung and bladder. 2) C-terminal region of EFEMP1 formed nonbranching fibrils. 3) Many proteins were identified from amyloid-laden tissues by mass spectrometry. 4) FSB staining and immunohistochemistry with anti EFEMP1 antibodies are superior to detect EFEMP1 amyloid deposits in tissues.

Academic Significance and Societal Importance of the Research Achievements

本研究では、新規アミロイド原因タンパク質としてEFEMP1を同定し、本アミロイドーシスの病態の一端を明らかにした。これまで、長年見過ごされていた病態を解明できたことで、本研究の成果は、今後の治療法や検査法の開発に繋がると考えられる。また、本研究成果が評価され、EFEMP1は新型のアミロイド原因タンパク質として、国際アミロイドーシス学会のアミロイド分類委員会より承認を得た（*Benson et al., Amyloid 2020）。アミロイドーシス研究において、新たなアミロイド原因タンパク質を見出したことは極めて重要な成果であり、アミロイド形成メカニズムを明らかにするのに役立つことが期待される。

Research Products

• [Int'l Joint Research] University of Pavia(イタリア)
• [Int'l Joint Research] University of Pavia(イタリア)
• [Int'l Joint Research] University of Pavia(イタリア)
• [Journal Article] EGF-containing fibulin-like extracellular matrix protein 1 amyloid incidentally found in surgically resected specimens of Colon cancer: a case report emphasising on an unrecognised type (2021)
  • Author(s): Tsukamoto Yoshitane、Tasaki Masayoshi、Fujii Hitoshi、Tsujie Masaki、Ueda Mitsuharu
  • Journal Title: Amyloid Volume: 28 Issue: 2 Pages: 136-137
  • DOI: 10.1080/13506129.2020.1841624
  • Peer Reviewed
• [Journal Article] Apolipoprotein AI amyloid deposits in the ligamentum flavum in patients with lumbar spinal canal stenosis (2020)
  • Author(s): Tasaki Masayoshi、Okada Masamitsu、Yanagisawa Akihiro、Nomura Toshiya、Matsushita Hiroaki、Ueda Akihiko、Inoue Yasuteru、Masuda Teruaki、Misumi Yohei、Yamashita Taro、Nakamura Takayuki、Miyamoto Takeshi、Obayashi Konen、Ando Yukio、Ueda Mitsuharu
  • Journal Title: Amyloid Volume: 28 Issue: 2 Pages: 1-6
  • DOI: 10.1080/13506129.2020.1858404
  • Peer Reviewed / Open Access
• [Journal Article] Simple, reliable detection of amyloid in fat aspirates using the fluorescent dye FSB: prospective study in 206 patients. (2019)
  • Author(s): Tasaki M, Milani P, Foli A, Verga L, Obici L, Basset M, Bozzola M, Ferraro G, Nuvolone M, Morbini P, Capello G, Ueda M, Obayashi K, Paulli M, Ando Y, Merlini G, Palladini G, Lavatelli F.
  • Journal Title: Blood Volume: 134 Issue: 3 Pages: 320-323
  • DOI: 10.1182/blood.2019000420
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1 (2019)
  • Author(s): Tasaki M, Ueda M, Hoshii Y, Mizukami M, Matsumoto S, Nakamura M, Yamashita T, Ueda A, Misumi Y, Masuda T, Inoue Y, Torikai T, Nomura T, Tsuda Y, Kanenawa K, Isoguchi A, Okada M, Matsui H, Obayashi K, Ando Y.
  • Journal Title: The Journal of Pathology Volume: 247 Issue: 4 Pages: 444-455
  • DOI: 10.1002/path.5203
  • Peer Reviewed
• [Journal Article] Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient. (2019)
  • Author(s): Swuec P, Lavatelli F, Tasaki M, Paissoni C, Rognoni P, Maritan M, Brambilla F, Milani P, Mauri P, Camilloni C, Palladini G, Merlini G, Ricagno S, Bolognesi M.
  • Journal Title: Nature Communiations Volume: 10 Issue: 1 Pages: 1269-1269
  • DOI: 10.1038/s41467-019-09133-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ATR-FTIR Spectroscopy Supported by Multivariate Analysis for the Characterization of Adipose Tissue Aspirates from Patients Affected by Systemic Amyloidosis (2019)
  • Author(s): Ami D, Mereghetti P, Foli A, Tasaki M, Milani P, Nuvolone M, Palladini G, Merlini G, Lavatelli F, Natalello A
  • Journal Title: Analytical Chemistry Volume: 91 Issue: 4 Pages: 2894-2900
  • DOI: 10.1021/acs.analchem.8b05008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic and clinical characteristics of hereditary transthyretin amyloidosis in endemic and non-endemic areas: experience from a single-referral center in Japan. (2018)
  • Author(s): Yamashita T, Ueda M, Misumi Y, Masuda T, Nomura T, Tasaki M, Takamatsu K, Sasada K, Obayashi K, Matsui H, Ando Y.
  • Journal Title: Journal of Neurology Volume: 265 Issue: 1 Pages: 134-140
  • DOI: 10.1007/s00415-017-8640-7
  • Peer Reviewed / Open Access
• [Journal Article] Sushi repeat-containing protein 1: a novel disease-associated molecule in cerebral amyloid angiopathy. (2017)
  • Author(s): Inoue Y, Ueda M, Tasaki M, Takeshima A, Nagatoshi A, Masuda T, Misumi Y, Kosaka T, Nomura T, Mizukami M, Matsumoto S, Yamashita T, Takahashi H, Kakita A, Ando Y.
  • Journal Title: Acta Neuropathologica Volume: 134 Issue: 4 Pages: 605-617
  • DOI: 10.1007/s00401-017-1720-z
  • Peer Reviewed / Open Access
• [Journal Article] Serum amyloid P component: A novel potential player in vessel degeneration in CADASIL. (2017)
  • Author(s): Nagatoshi A, Ueda M, Ueda A, Tasaki M, Inoue Y, Ma Y, Masuda T, Mizukami M, Matsumoto S, Kosaka T, Kawano T, Ito T, Ando Y.
  • Journal Title: Journal of the Neurological Sciences Volume: 379 Pages: 69-76
  • DOI: 10.1016/j.jns.2017.05.033
  • Peer Reviewed
• [Journal Article] A novel transthyretin variant V28S (p.V48S) with a double-nucleotide substitution in the same codon. (2017)
  • Author(s): Okada M, Misumi Y, Ueda M, Yamashita T, Masuda T, Tasaki M, Ando Y.
  • Journal Title: Amyloid Volume: 24 Issue: 4 Pages: 231-232
  • DOI: 10.1080/13506129.2017.1381082
  • Peer Reviewed
• [Presentation] EGF-containing fibulin-like extracellular matrix protein 1: A novel age-related amyloid precursor protein (2020)
  • Author(s): Masayoshi Tasaki, Mitsuharu Ueda, Yoshinobu Hoshii, Aito Isoguchi, Toshiya Nomura, Masamitsu Okada, Yasuteru Inoue, Teruaki Masuda, Yohei Misumi, Taro Yamashita, Konen Obayashi, Yukio Ando
  • Organizer: The XVII International Symposium On Amyloidosis
  • Int'l Joint Research
• [Presentation] EFEMP1アミロイドの沈着頻度および至適病理学的診断法の検討 (2019)
  • Author(s): 田崎雅義、植田光晴、大林光念、安東由喜雄
  • Organizer: 第66回日本臨床検査医学会学術集会
• [Presentation] 質量分析装置を用いた新規アミロイド原因蛋白質、EFEMP1の同定 (2019)
  • Author(s): 田崎雅義、植田光晴、星井嘉信、磯口藍斗、山下太郎、大林光念、安東由喜雄
  • Organizer: 第59回日本臨床化学会学術集会
• [Presentation] EFEMP1 C末端領域のアミロイド形成能および細胞毒性 (2019)
  • Author(s): 田崎雅義、礒口藍斗、植田光晴、星井嘉信、岡田匡充、野村隼也、井上泰輝、増田曜章、三隅洋平、山下太郎、大林光念、安東由喜雄
  • Organizer: 第7回日本アミロイドーシス学会学術集会
• [Presentation] アミロイドーシスの診断法開発と臨床応用 (2019)
  • Author(s): 田崎雅義
  • Organizer: 第66回日本臨床検査医学会学術集会
  • Invited
• [Presentation] Characteristics of TTR fragmentation pattern in ATTR patients carrying various mutations (2018)
  • Author(s): Masayoshi Tasaki, Francesca Lavatelli, Angelo M. Minnella, Marco Di Girolamo, Elena Antoniazzi, Margerita Bozzola, Giovanni Ferraro, Mario Nuvolone, Giovanni Palladini, Konen Obayashi, Yukio Ando, Giampaolo Merlini, Laura Obici
  • Organizer: XVIth International Symposium on Amyloidosis
  • Int'l Joint Research
• [Book] 21世紀の疾患： 神経関連アミロイドーシス (2020)
  • Author(s): 安東由喜雄、礒口藍斗、一木裕子、井上泰輝、植田光晴、大林光念、岡田匡充、城野博史、田崎雅義、野村隼也、増田曜章、松下博昭、三隅洋平、山下太郎、渡邊礼美
  • Total Pages: 136
  • Publisher: 医学と看護社
  • ISBN: 9784909888075