Modeling immunoglobulin light chain amyloidosis in Caenorhabditis elegans

Cardiomyopathy determines the prognosis of patients withimmunoglobulin light chain (AL) amyloidosis, a rare systemicdisease caused by the misfolding and deposition of monoclonallight chains (LCs). The reasons underlying their cardiac tropismremain unknown, and an animal model recapitulating the main pathological features of AL amyloidosis is needed. Taking advantageof the similarities between the vertebrate cardiac muscle andCaenorhabditis elegans pharynx, we developed a new transgenicnematode expressing a human amyloidogenic λ LC, the sequence ofwhich was deduced from a patient with AL amyloidosis with cardiacinvolvement (MNH). Strains expressing a non-amyloidogenic LC(MNM) or the empty vector only (MNV) were generated as controls. Atvariance with controls, LCs expressed in the body-wall muscle ofMNH worms formed soluble dimeric assemblies, which could besecreted and reach different organs. Notably, MNH worms exerted apharyngeal impairment resembling cardiac functional dysfunction inpatients with AL amyloidosis, accompanied by increased radicaloxygen species production and tissue ultrastructural damage. Thisnewanimal model could help to elucidate the mechanisms underlyingthe cardiac-specific toxicity occurring in AL amyloidosis, providinginnovative insights into the pathophysiology.