Modeling immunoglobulin light chain amyloidosis inCaenorhabditis 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 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 and C. elegans’ pharynx, we developed a new transgenic nematode expressing a human amyloidogenic λ LC whose sequence was deduced from a patient suffering from 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 native soluble dimeric assemblies, which were secreted and reached different organs, including the pharynx. Noteworthy, MNH worms exerted a pharyngeal impairment resembling cardiac functional impairment occurring in patients with AL, 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. Competing Interest Statement M.R., M.M.B., A.C., S.M., N.V., C.N., A.Conz., and F.F. declare no competing financial interests. M.S. and L.D. have two patents (20190343825, WO/2018/000047, and 2017288056) related to this work. Footnotes The section on Abstract was shortened; the Section on Materials and Methods was changed position; Figure 2 was revised.