Abstract

Light chain amyloidosis is one of the unique examples within amyloid diseases where the amyloidogenic precursor is a protein that escapes the quality control machinery and is secreted from the cells to be circulated in the bloodstream. The immunoglobulin light chains are produced by an abnormally proliferative monoclonal population of plasma cells that under normal conditions produce immunoglobulin molecules such as IgG, IgM or IgA. Once the light chains are in circulation, the proteins misfold and deposit as amyloid fibrils in numerous tissues and organs, causing organ failure and death. While there is a correlation between the thermodynamic stability of the protein and the kinetics of amyloid formation, we have recently found that this correlation applies within a thermodynamic range, and it is only a helpful correlation when comparing mutants from the same protein. Light chain amyloidosis poses unique challenges because each patient has a unique protein sequence as a result of the selection of a germline gene and the incorporation of somatic mutations. The exact location of the misfolding process is unknown as well as the full characterization of all of the toxic species populated during the amyloid formation process in light chain amyloidosis.

Keywords: Light chain amyloidosis, immunoglobulin light chain, somatic mutations, amyloid formation, dimer