Biological molecules enhancing/inhibiting amyloid fibril formation: Integration of in vitro experiment and proteomic analysis

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06967
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: University of Fukui
• Principal Investigator: Naiki Hironobu 福井大学, 学術研究院医学系部門, 教授 (10227704)
• Co-Investigator(Kenkyū-buntansha): 植田 光晴 熊本大学, 大学院生命科学研究部(医), 教授 (60452885)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: アミロイドーシス / β2-ミクログロブリン / プロテオーム解析 / 免疫染色 / プロテオグリカン

Outline of Final Research Achievements

We first showed that in addition to high serum β2-microglobulin (β2-m) levels and a long dialysis vintage as the primary and secondary risk factors for the onset of dialysis-related amyloidosis (DRA), respectively, decreased serum albumin concentration in dialysis patients is the tertiary risk factor. Next, we showed that class I small leucine-rich proteoglycans (SLRPs) (decorin, biglycan and asporin) colocalize with β2-m amyloid deposits. We suggested that the core protein of SLRPs could enhance the deposition of β2-m amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of β2-m in the fibrils, as well as by acting as a scaffold for the polymerization of β2-m into the fibrils. Finally, we reported the first case with transthyretin amyloid cardiomyopathy complicated with rapidly progressive aortic stenosis possibly caused by transthyretin amyloid deposition in the aortic valve.

Free Research Field

病理学

Academic Significance and Societal Importance of the Research Achievements

本研究で得られた上記成果は、単にβ2-mアミロイドーシスのみならず、ヒトアミロイドーシスに共通する発症機構の解明や治療戦略の構築に向け、有益な示唆をもたらした。また、本研究で得られた新たな実験ツールは、他のヒトアミロイドーシス発症機構解明に向けた研究にも普遍的に活用することが出来、本研究の学術的波及効果は大きいと考える。さらに、厚労省指定難病である全身性アミロイドーシスの治療法開発にも貢献し、社会的意義も大きいと考える。