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

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 h...

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Autores principales:	Ramella, Nahuel Alberto, Schinella, Guillermo, Ferreira, Sergio T., Prieto, Eduardo Daniel, Vela, María Elena, Ríos, José Luis, Tricerri, María Alejandra, Rimoldi, Omar Jorge
Formato:	Articulo
Lenguaje:	Inglés
Publicado:	2012
Materias:	Ciencias Médicas Medicina macrophage activation polyneuropathy protein aggregation Amino Acid Substitution Amyloidogenic Proteins Protein Folding Protein Multimerization Protein Stability
Acceso en línea:	http://sedici.unlp.edu.ar/handle/10915/34069 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0043755
Aporte de:	SEDICI (UNLP) de Universidad Nacional de La Plata

id	I19-R120-10915-34069
record_format	dspace
institution	Universidad Nacional de La Plata
institution_str	I-19
repository_str	R-120
collection	SEDICI (UNLP)
language	Inglés
topic	Ciencias Médicas Medicina macrophage activation polyneuropathy protein aggregation Amino Acid Substitution Amyloidogenic Proteins Protein Folding Protein Multimerization Protein Stability
spellingShingle	Ciencias Médicas Medicina macrophage activation polyneuropathy protein aggregation Amino Acid Substitution Amyloidogenic Proteins Protein Folding Protein Multimerization Protein Stability Ramella, Nahuel Alberto Schinella, Guillermo Ferreira, Sergio T. Prieto, Eduardo Daniel Vela, María Elena Ríos, José Luis Tricerri, María Alejandra Rimoldi, Omar Jorge Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity
topic_facet	Ciencias Médicas Medicina macrophage activation polyneuropathy protein aggregation Amino Acid Substitution Amyloidogenic Proteins Protein Folding Protein Multimerization Protein Stability
description	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.
format	Articulo Articulo
author	Ramella, Nahuel Alberto Schinella, Guillermo Ferreira, Sergio T. Prieto, Eduardo Daniel Vela, María Elena Ríos, José Luis Tricerri, María Alejandra Rimoldi, Omar Jorge
author_facet	Ramella, Nahuel Alberto Schinella, Guillermo Ferreira, Sergio T. Prieto, Eduardo Daniel Vela, María Elena Ríos, José Luis Tricerri, María Alejandra Rimoldi, Omar Jorge
author_sort	Ramella, Nahuel Alberto
title	Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity
title_short	Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity
title_full	Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity
title_fullStr	Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity
title_full_unstemmed	Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity
title_sort	human apolipoprotein a-i natural variants: molecular mechanisms underlying amyloidogenic propensity
publishDate	2012
url	http://sedici.unlp.edu.ar/handle/10915/34069 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0043755
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bdutipo_str	Repositorios
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Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity

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