Conformation of human apolipoprotein A-I amyloid variants: folding and the role of inflammation in the protein aggregation disease

RAMELLA, N.A.; GISELA M. GADDI; SCHINELLA, GR; GABRIELA S. FINARELLI; TRICERRI, M.A.; ROSÚ, S.A.; PRIETO, E.D.; CURTO L.M.; GISONNO, RA; GORGOJO, JP; M. FERNANDA CORTEZ; RODRIGUEZ, MARIA EUGENIA

Simposio; XVII International Symposium of Amyloidosis; 2020

The reasons that determine the pathological deposition of human apolipoprotein A-I variantsinducing organ failure have been under research since the early description of natural mutationsin patients. Different protein conformations may be involved in the development of clinicalmanifestations associated with human amyloidosis. Although a fibrillar conformation is usually thesignature of damage in the tissues, it is not clear whether this species isper sethe cause or theconsequence of the disease. From the more than 20 amyloidogenic variants of apoA-I described(Figure 1), a mutation leading to a deletion at position 107 (Lys107-0) has a unique pattern, aspatients carrying this variant show amyloidosis and severe atherosclerosis. Here we intended tocharacterize protein aggregation structures, and to test the hypothesis that a pro-inflammatorymicroenvironment could favor protein misfolding.Conclusions: -Even though we obtained well-defined fibrillar conformations, the final, insoluble conformation might not be attained. -Protein oxidation under H2O2induces the formation of well-defined fibrillar species. -Fibrillar Lys107-0 ox variant is active to induce macrophage activation.Thus, it could be postulated that a pro-oxidant scenario (probably set by chronic atherosclerotic plaques), may help theformation of fibrillar species which in addition may induce the settlement of local inflammatory landscape, thus acting as apositive feed-back helping to establish the tissue lesion