title: C. elegans expressing human β2-microglobulin: a novel model for studying the relationship between the molecular assembly and the toxic phenotype.
abstract: Availability of living organisms to mimic key step of amyloidogenesis of human protein has become an indispensable tool for our translation approach aiming at filling the deep gap existing between the biophysical and biochemical data obtained in vitro and the pathological features observed in patients. Human β(2)-microglobulin (β(2)-m) causes systemic amyloidosis in haemodialysed patients. The structure, misfolding propensity, kinetics of fibrillogenesis and cytotoxicity of this protein, in vitro, have been studied more extensively than for any other globular protein. However, no suitable animal model for β(2)-m amyloidosis has been so far reported. We have now established and characterized three new transgenic C. elegans strains expressing wild type human β(2)-m and two highly amyloidogenic isoforms: P32G variant and the truncated form ΔN6 lacking of the 6 N-terminal residues. The expression of human β(2)-m affects the larval growth of C. elegans and the severity of the damage correlates with the intrinsic propensity to self-aggregate that has been reported in previous in vitro studies. We have no evidence of the formation of amyloid deposits in the body-wall muscles of worms. However, we discovered a strict correlation between the pathological phenotype and the presence of oligomeric species recognized by the A11 antibody. The strains expressing human β(2)-m exhibit a locomotory defect quantified with the body bends assay. Here we show that tetracyclines can correct this abnormality confirming that these compounds are able to protect a living organism from the proteotoxicity of human β(2)-m.
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Diomede
authors.forename: Cristina
authors.initials: C
authors.lastname: Soria
authors.forename: Margherita
authors.initials: M
authors.lastname: Romeo
authors.forename: Sofia
authors.initials: S
authors.lastname: Giorgetti
authors.forename: Loredana
authors.initials: L
authors.lastname: Marchese
authors.forename: Patrizia Palma
authors.initials: PP
authors.lastname: Mangione
authors.forename: Riccardo
authors.initials: R
authors.lastname: Porcari
authors.forename: Irene
authors.initials: I
authors.lastname: Zorzoli
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
authors.forename: Monica
authors.initials: M
authors.lastname: Stoppini
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006801:Humans; D008856:Microscopy, Fluorescence; D001613:beta 2-Microglobulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D001613:beta 2-Microglobulin