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

RAMELLA, N. A.; RIMOLDI, O. J.; SCHINELLA, G. R.; PRIETO, E. D.; ROSU, S. A.; VELA, M. E.; TRICERRI, M. A.

Tucuman

Simposio; XLI Reunión Científica Anual de la Sociedad Argentina de Biofísica; 2012

SAB

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 induce 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. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of wild type apoA-I (Wt) and two natural variants, apoA-IGly26Arg, associated with polyneuropathy and kidney dysfunction, and apoA-ILys107-0, implicated in amyloidosis in severe atherosclerosis. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. Both pathological variants share common structural properties including decreased stability compared to Wt and a more flexible structure. Interestingly, however, distinct features appear to determine their pathogenic mechanisms, including a different tendency to elicit local chronic inflammation response from macrophages. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce amyloidosis as a consequence of the pro-inflammatory microenvironment associated to atherogenesis. In addition, it should be considered that misfolded proteins could mediate selective cell signaling events, determining an intricate cross-talk between function and pathogenicity.