title: The intracellular quality control system down-regulates the secretion of amyloidogenic apolipoprotein A-I variants: a possible impact on the natural history of the disease.
abstract: Hereditary systemic amyloidosis caused by apolipoprotein A-I variants is a dominantly inherited disease characterised by fibrillar deposits mainly localized in the kidneys, liver, testis and heart. We have previously shown that the apolipoprotein A-I variant circulates in plasma at lower levels than the wild-type form (Mangione et al., 2001; Obici et al., 2004) thus raising the possibility that the amyloid deposits could sequester the circulating amyloidogenic chain or that the intracellular quality control can catch and capture the misfolded amyloidogenic chain before the secretion. In this study we have measured plasma levels of the wild-type and the variant Leu75Pro apolipoprotein A-I in two young heterozygous carriers in which tissue amyloid deposition was still absent. In both cases, the mutant was present at significantly lower levels than the wild-type form, thus indicating that the low plasma concentration of the apolipoprotein A-I variant is not a consequence of the protein entrapment in the amyloid deposits. In order to explore the cell secretion of amyloidogenic apolipoprotein A-I variants, we have studied COS-7 cells expressing either wild-type apolipoprotein A-I or two amyloidogenic mutants: Leu75Pro and Leu174Ser. Quantification of intracellular and extracellular apolipoprotein A-I alongside the intra-cytoplasmatic localization indicates that, unlike the wild-type protein, both variants are retained within the cells and mainly accumulate in the endoplasmic reticulum. The low plasma concentration of amyloidogenic apolipoprotein A-I may therefore be ascribed to the activity of the intracellular quality control that represents a first line of defence against the secretion of pathogenic variants.
authors.affiliation: Department of Pharmacological Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Marchesi
authors.forename: Cinzia
authors.initials: C
authors.lastname: Parolini
authors.forename: Caterina
authors.initials: C
authors.lastname: Valetti
authors.forename: Palma
authors.initials: P
authors.lastname: Mangione
authors.forename: Laura
authors.initials: L
authors.lastname: Obici
authors.forename: Sofia
authors.initials: S
authors.lastname: Giorgetti
authors.forename: Sara
authors.initials: S
authors.lastname: Raimondi
authors.forename: Simona
authors.initials: S
authors.lastname: Donadei
authors.forename: Gina
authors.initials: G
authors.lastname: Gregorini
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.forename: Monica
authors.initials: M
authors.lastname: Stoppini
authors.forename: Giulia
authors.initials: G
authors.lastname: Chiesa
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000682:Amyloid / Q000378:metabolism; D028226:Amyloidosis, Familial / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006579:Heterozygote; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008856:Microscopy, Fluorescence; D009154:Mutation
chemical_list: D000682:Amyloid; D016632:Apolipoprotein A-I