Modeling immunoglobulin light chain amyloidosis in Caenorhabditis elegans.

Abstract

Cardiomyopathy determines the prognosis of patients with immunoglobulin light chain (AL) amyloidosis, a rare systemic disease caused by the misfolding and deposition of monoclonal light chains (LCs). The reasons underlying their cardiac tropism remain unknown, and an animal model recapitulating the main pathological features of AL amyloidosis is needed. Taking advantage of the similarities between the vertebrate cardiac muscle and Caenorhabditis elegans pharynx, we developed a new transgenic nematode expressing a human amyloidogenic λ LC, the sequence of which was deduced from a patient with AL amyloidosis with cardiac involvement (MNH). Strains expressing a non-amyloidogenic LC (MNM) or the empty vector only (MNV) were generated as controls. At variance with controls, LCs expressed in the body-wall muscle of MNH worms formed soluble dimeric assemblies, which could be secreted and reach different organs. Notably, MNH worms exerted a pharyngeal impairment resembling cardiac functional dysfunction in patients with AL amyloidosis, accompanied by increased radical oxygen species production and tissue ultrastructural damage. This new animal model could help to elucidate the mechanisms underlying the cardiac-specific toxicity occurring in AL amyloidosis, providing innovative insights into the pathophysiology.