Biopsy-resolved cryo-EM structures of amyloid fibrils provide molecular insights into AL amyloidosis

• 成果类型: Article
• 署名作者: Yao, Yuxuan; Zhao, Qinyue; Yao, Shun; Xu, Yamei; Liu, Kaien; Cao, Tianyi; Sun, Bo; Zhou, Jingmin; Liu, Cong; Li, Dan
• 署名单位: Shanghai Jiao Tong University; Shanghai Jiao Tong University; Fudan University; Fudan University; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; ShanghaiTech University; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2515454123
• 发表日期: 2026-01-13
• 页码: e2515454123
• 关键词: systemic light chain amyloidosis; -electron microscopy; amyloid fibril structure; biopsy tissues; LIGHT-CHAIN AMYLOIDOSIS; SYSTEMIC AMYLOIDOSIS; posttranslational modifications; mass-spectrometry; STAGING SYSTEM; sequence; serum; aggregation; diagnosis; gene

摘要

Systemic light chain amyloidosis (AL) is characterized by amyloid fibril deposition in multiple organs, often severely affecting cardiac function. In this study, we extracted amyloid fibrils directly from abdominal fat and cardiac tissue biopsies obtained from three AL patients. Using cryo-electron microscopy, we determined five distinct structures of light chain (LC) amyloid fibrils. Our results demonstrate that LC fibrils from different patients adopt unique structural conformations, highlighting patient-specific fibril variations. Conversely, LC fibrils extracted from different tissues within the same patient share highly similar overall fibril structures, yet exhibit localized conformational variations, potentially shaped by distinct environmental cofactors. This study emphasizes the combined roles of patient-specific protein sequences and tissue-specific microenvironments in defining LC fibril conformation. The determination of LC fibril structures directly from easily accessible abdominal fat biopsy provides critical molecular insights into AL amyloidosis pathology, facilitating the development of therapeutic strategies.