Dissecting the Molecular Features of Systemic Light Chain (AL) Amyloidosis: Contributions from Proteomics

Abstract

Amyloidoses are characterized by aggregation of proteins into highly ordered amyloid fibrils, which deposit in the extracellular space of tissues, leading to organ dysfunction. In AL (amyloid light chain) amyloidosis, the most common form in Western countries, the amyloidogenic precursor is a misfolding-prone immunoglobulin light chain (LC), which, in the systemic form, is produced in excess by a plasma cell clone and transported to target organs though blood. Due to the primary role that proteins play in the pathogenesis of amyloidoses, mass spectrometry (MS)-based proteomic studies have gained an established position in the clinical management and research of these diseases. In AL amyloidosis, in particular, proteomics has provided important contributions for characterizing the precursor light chain, the composition of the amyloid deposits and the mechanisms of proteotoxicity in target organ cells and experimental models of disease. This review will provide an overview of the major achievements of proteomic studies in AL amyloidosis, with a presentation of the most recent acquisitions and a critical discussion of open issues and ongoing trends.

Molecular Mechanisms of Cardiac Amyloidosis

“…Moreover, several other proteins, such as heparan sulphate proteoglycan and serum amyloid P-component, are always co-deposited with amyloid fibrils [ 11 ]. Recent development of proteomic analyses have revealed proteins included in amyloid deposits [ 12 , 13 ].…”

“…Both λ and κ LC form homodimers via disulfide bond [ 73 ]. The majority (approximately 75%) of all monoclonal amyloidogenic LC are λ isotype [ 13 , 74 ]. Some groups have shown unfolding of the LC structure in amyloid fibrils from AL amyloidosis patients using cryo-electron microscopy [ 75 , 76 , 77 ].…”