Modeling immunoglobulin light chain amyloidosis inCaenorhabditis elegans

Abstract

Cardiac involvement determines the survival 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 underlining their cardiac tropism remain unknown, and an animal model recapitulating the main pathological features of AL amyloidosis is instrumental. Taking advantage of the similarities between the vertebrate heart andC. elegans’ pharynx, we developed a new transgenic nematode expressing a human amyloidogenic λ LC whose sequence was deduced from an AL-affected patient 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 native soluble dimeric assemblies, which were secreted and reached different organs, including the pharynx. Noteworthy, MNH worms exerted a pharyngeal impairment resembling the bradycardia occurring in AL-affected patients, accompanied by increased radical oxygen species production and tissue ultrastructural damage. This new animal model can allow the elucidation of the mechanisms underlying the cardiac-specific tropism occurring in AL amyloidosis, providing innovative insights into the pathophysiology.Summary StatementWe generated a newC. elegansanimal model of cardiac AL amyloidosis. This model represents a uniquein vivotool for studying the cardiac-specific damage occurring in the disease.