Fibrillar conformation of an apolipoprotein A-I variant involved in amyloidosis and atherosclerosis

GISONNO, R.; PRIETO, E. D.; GORGOJO, J.P; CURTO, L. M.; RODRIGUEZ, M. E.; ROSU, S. A.; GADDI, G. M.; FINARELLI, G. S.; CORTEZ, M. F; SCHINELLA, G; RAMELLA, N.; TRICERRI, MARIA ALEJANDRA

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2019 vol. 1864

0304-4165

Background: Different protein conformations may be involved in the development of clinical manifestations associatedwith human amyloidosis. Although a fibrillar conformation is usually the signature of damage in the tissuesof patients, it is not clear whether this species is per se the cause or the consequence of the disease. Hereditaryamyloidosis due to variants of apolipoprotein A-I (apoA-I) with a substitution of a single amino acid is characterizedby the presence of fibrillar protein within the lesions. Thus mutations result in increased protein aggregation.Here we set up to characterize the folding of a natural variant with a mutation leading to a deletion at position107 (apoA-I Lys107?0). Patients carrying this variant show amyloidosis and severe atherosclerosis.Methods: We oxidized this variant under controlled concentrations of hydrogen peroxide and analyzed the structureobtained after 30-day incubation by fluorescence, circular dichroism and microscopy approaches. Neutrophilsactivation was characterized by confocal microscopy.Results: We obtained a high yield of well-defined stable fibrillar structures of apoA-I Lys107?0. In an in vitro neutrophilssystem, we were able to detect the induction of Neutrophils Extracellular Traps (NETs) when we incubatedwith oxidized apoA-I variants. This effect was exacerbated by the fibrillar structure of oxidized Lys 107?0.Conclusions: We conclude that a pro-inflammatory microenvironment could result in the formation of aggregation-prone species, which, in addition may induce a positive feed-back in the activation of an inflammatory response.General significance: These events may explain a close association between amyloidosis due to apoA-I Lys107?0and atherosclerosis.