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

NAHUEL A. RAMELLA; RIMOLDI, OMAR; SCHINELLA, GUILLERMO; PRIETO E.D; ROSU, SILVANA; VELA, M.E; TRICERRI MA

San Javier, Tucumán

Congreso; XLI Reunión Anual de la SAB 2012,; 2012

Human apolipoprotein A&I (apoA&I)&derived amyloidos is can present with either wild&type (Wt) protein deposits in atherosclerotic plaques or as a hereditary form in which apoA&I var iants induce multiple organ failure. More than 15 single amino acid repla cement amyloidogenic apoA&I variants have been described, but the molecular mechanisms involved in amyloid&associated pathology remain lar gely unknown. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironmen t associated with chronic inflammation on the folding and pro&amyloid ogenic processing of wild type apoA&I (Wt) and two natural variants, apo A&IGly26Arg, associated with polyneuropathy and kidney dysfuncti on, and apoA&ILys107&0, implicated in amyloidosis in severe athe rosclerosis. Results showed that mildly acidic pH promotes misfolding, a ggregation, and increased binding of apoA&I to extracellular matrix elements. In addition, activated neutrophils and oxidative/proteolytic cle avage of the protein give rise to pro amyloidogenic products. Both pathologic al variants share common structural properties including decreased st ability compared to Wt and a more flexible structure. Interestingly, howev er, distinct features appear to determine their pathogenic mechanisms, in cluding a different tendency to elicit local chronic inflammation respo nse from macrophages.We conclude that, even though apoA&I is not inheren tly amyloidogenic, itmay produce amyloidosis as a consequence of the pro&inflammatorymicroenvironment associated to atherogenesis. In ad dition, it should beconsidered that misfolded proteins could mediate se lective cell signaling events, determining an intricate cross&talk between function and pathogenicity.