Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity

• Autores: Ramella, Nahuel Alberto; Schinella, Guillermo; Ferreira, Sergio T.; Prieto, Eduardo Daniel; Vela, María Elena; Ríos, José Luis; Tricerri, María Alejandra; Rimoldi, Omar Jorge
• Año de publicación: 2012
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Ciencias Médicas; Medicina; macrophage activation; polyneuropathy; protein aggregation; Amino Acid Substitution; Amyloidogenic Proteins; Protein Folding; Protein Multimerization; Protein Stability
• Institución: Universidad Nacional de La Plata

Human apolipoprotein A-I (apoA-I)-derived amyloidosis can present with either wild-type (Wt) protein deposits in atherosclerotic plaques or as a hereditary form in which apoA-I variants deposit causing multiple organ failure. More than 15 single amino acid replacement amyloidogenic apoA-I variants have been described, but the molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here, we have investigated by fluorescence and biochemical approaches the stabilities and propensities to aggregate of two disease-associated apoA-I variants, apoA-IGly26Arg, associated with polyneuropathy and kidney dysfunction, and apoA-ILys107-0, implicated in amyloidosis in severe atherosclerosis. Results showed that both variants share common structural properties including decreased stability compared to Wt apoA-I and a more flexible structure that gives rise to formation of partially folded states. Interestingly, however, distinct features appear to determine their pathogenic mechanisms. ApoA-ILys107-0 has an increased propensity to aggregate at physiological pH and in a pro-inflammatory microenvironment than Wt apoA-I, whereas apoA-IGly26Arg elicited macrophage activation, thus stimulating local chronic inflammation. Our results strongly suggest that some natural mutations in apoA-I variants elicit protein tendency to aggregate, but in addition the specific interaction of different variants with macrophages may contribute to cellular stress and toxicity in hereditary amyloidosis.
Facultad de Ciencias Médicas