title: A Caenorhabditis elegans-based assay recognizes immunoglobulin light chains causing heart amyloidosis.
abstract: Poor prognosis and limited therapeutic options characterize immunoglobulin light-chain (AL) amyloidosis with major heart involvement. Reliable experimental models are needed to study light-chain (LC)/heart interactions and to explore strategies for prevention of cardiac damage. We have exploited the nematode Caenorhabditis elegans as a novel tool, because its pharynx is evolutionarily related to the vertebrate heart. Our data demonstrate that the pharyngeal pumping of C elegans is significantly and selectively reduced by LCs from AL patients suffering from cardiomyopathy, but not by amyloid LCs with different organ tropism or nonamyloidogenic LCs from multiple myeloma. This functional alteration is dependent on the LC concentration and results in persistent pharyngeal dysfunction and in a significant reduction of the worms' lifespan. These manifestations are paralleled by an increase of mitochondrial reactive oxygen species and can be prevented by treatment with antioxidant agents. In conclusion, these data indicate that this nematode-based assay is a promising surrogate model for investigating the heart-specific toxicity of amyloidogenic LCs and for a rapid screening of new therapeutic strategies.
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy;
authors.forename: Luisa
authors.initials: L
authors.lastname: Diomede
authors.affiliation: Amyloid Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy;
authors.forename: Paola
authors.initials: P
authors.lastname: Rognoni
authors.affiliation: Amyloid Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Lavatelli
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy;
authors.forename: Margherita
authors.initials: M
authors.lastname: Romeo
authors.affiliation: Department of Medical Biotechnology and Translational Medicine University of Milan, Laboratorio Interdisciplinare Tecnologie Avanzate, Segrate, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: del Favero
authors.affiliation: Department of Medical Biotechnology and Translational Medicine University of Milan, Laboratorio Interdisciplinare Tecnologie Avanzate, Segrate, Italy;
authors.forename: Laura
authors.initials: L
authors.lastname: Cantù
authors.affiliation: Department of Chemistry, University of Turin, Turin, Italy;
authors.forename: Elena
authors.initials: E
authors.lastname: Ghibaudi
authors.affiliation: Amyloid Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy;
authors.forename: Andrea
authors.initials: A
authors.lastname: di Fonzo
authors.affiliation: Bio-imaging Unit, Department of Cardiovascular Research, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy; Renal Research Laboratory, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Ospedale Maggiore Policlinico and Fondazione D'Amico per la Ricerca sulle Malattie Renali, Milan, Italy;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Corbelli
authors.affiliation: Bio-imaging Unit, Department of Cardiovascular Research, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy;
authors.forename: Fabio
authors.initials: F
authors.lastname: Fiordaliso
authors.affiliation: Amyloid Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Italy; and.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palladini
authors.affiliation: Amyloid Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy;
authors.forename: Veronica
authors.initials: V
authors.lastname: Valentini
authors.affiliation: Medical Oncology Unit, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Perfetti
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche "Mario Negri," Milan, Italy;
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Amyloid Research and Treatment Center, Foundation Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Italy; and.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
mesh_terms: D000328:Adult; D000368:Aged; D000686:Amyloidosis / Q000175:diagnosis* / Q000276:immunology; D000818:Animals; D001681:Biological Assay; D017173:Caenorhabditis elegans; D054715:Cardiotoxins / Q000302:isolation & purification / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006331:Heart Diseases / Q000175:diagnosis* / Q000276:immunology; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology; D010614:Pharynx / Q000166:cytology / Q000187:drug effects / Q000502:physiology
chemical_list: D054715:Cardiotoxins; D007147:Immunoglobulin Light Chains