Details

Autor(en) / Beteiligte

• Ramella, Nahuel A
• Schinella, Guillermo R
• Ferreira, Sergio T
• Prieto, Eduardo D
• Vela, María E
• Ríos, José Luis
• Tricerri, M Alejandra
• Rimoldi, Omar J
• Uversky, Vladimir N.

Titel

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

Ist Teil von

• PloS one, 2012-08, Vol.7 (8), p.e43755

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2012

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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.