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

ROMINA A. GISONNO; EDUARDO D. PRIETO; JUAN P. GORGOJO; LUCRECIA M. CURTO; RODRIGUEZ, MARIA EUGENIA; SILVANA A. ROSÚ; GISELA M. GADDI; GABRIELA S. FINARELLI; M. FERNANDA CORTEZ; GUILLERMO R. SCHINELLA; M. ALEJANDRA TRICERRI; NAHUEL A. RAMELLA

BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS

ELSEVIER SCIENCE BV

Año: 2020 vol. 1864

0304-4165

Background: Different protein conformations may be involved in the development of clinical manifestationsassociated with human amyloidosis. Although a fibrillar conformation is usually the signature of damage in thetissues of patients, it is not clear whether this species is per se the cause or the consequence of the disease.Hereditary amyloidosis due to variants of apolipoprotein A-I (apoA-I) with a substitution of a single amino acid ischaracterized by the presence of fibrillar protein within the lesions. Thus mutations result in increased proteinaggregation. Here we set up to characterize the folding of a natural variant with a mutation leading to a deletionat position 107 (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 thestructure obtained after 30-day incubation by fluorescence, circular dichroism and microscopy approaches.Neutrophils activation 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 neutrophils system, we were able to detect the induction of Neutrophils Extracellular Traps(NETs) when we incubated with oxidized apoA-I variants. This effect was exacerbated by the fibrillar structure ofoxidized 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 inflammatoryresponse.General significance: These events may explain a close association between amyloidosis due to apoA-I Lys107?0and atherosclerosis