Current and New Perspectives on the Molecular and Cellular Mechanisms of Amyloid Formation and Toxicity in Light Chain Amyloidosis

Abstract

Light chain (AL) amyloidosis is a protein misfolding disease characterized by the abnormal proliferation of monoclonal plasma cells that secrete free immunoglobulin light chains (LC) into circulation. These LCs misfold and aggregate as amyloid fibrils in vital organs. The process of amyloid formation causes organ failure, although the exact mechanism is unknown. The most frequently affected organs are the kidneys, heart, liver and peripheral nerves. AL amyloidosis is a devastating disease with a median survival of 12-40 months (Kumar et al., 2011; Wechalekar et al., 2008). The incidence of AL is 9 per million per year in the US, comparable to the incidence of Hodgkin’s Lymphoma. Current treatments are harsh and not curative (chemotherapy and autologous stem cell transplantation), targeting the plasma cells producing the protein. There is currently no treatment that targets the misfolding process or the amyloid fibrils. This chapter will discuss the latest developments in our understanding of the molecular mechanisms of AL amyloidosis including the role of mutations, cellular microenvironment, dimerization structures, different species populated in AL amyloid fibril formation, and light chain-associated cell and tissue toxicity. We will describe the challenges facing AL amyloidosis researchers to develop effective animal models of the disease and to find the best therapeutic strategies to treat this complex, devastating disease.