ABSTRACT
AL amyloidosis is a systemic disease caused by the aggregation of free antibody light chains (LC) secreted by aberrant plasma cell clones into the bloodstream. These LC aggregates form amyloid fibrils that deposit in multiple organs, leading to organ failure and, ultimately, death. Investigating the structural basis of LC aggregation is a critical avenue for understanding the biopathology of AL amyloidosis. Structural insights into AL fibril formation may reveal mechanisms driving amyloid deposition and inspire novel therapeutic strategies. Previous studies using cryo-electron microscopy have uncovered diverse AL fibril structures extracted from multiple patients, highlighting variability in fibril architecture. Here, we present a novel cryo-EM structure of AL cardiac fibrils from a patient with AL amyloidosis. This structure reveals a unique fibril fold and the coexistence of multiple morphologies, including single- and double-protofilament forms. Notably, some of these double-protofilament fibrils exhibit an uncommon rotational symmetry, raising intriguing questions about the mechanisms governing fibril formation and evolution over time.
Competing Interest Statement
L.S. consults for Intellia Therapeutics Inc. and Attralus Inc., and Advisory Board member for Alexion Pharmaceuticals and Pfizer. The remaining authors declare no competing interests.
