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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
Authors:Marta MarchesiCinzia Parolini  Caterina ValettiPalma Mangione  Laura ObiciSofia Giorgetti  Sara RaimondiSimona Donadei  Gina GregoriniGiampaolo Merlini  Monica StoppiniGiulia Chiesa  Vittorio Bellotti
Affiliation:
  • a Department of Pharmacological Sciences, Università degli Studi di Milano, via Balzaretti 9, 20133 Milan, Italy
  • b MicroSCoBiO Research Center and IFOM Center of Cell Oncology and Ultrastructure, Dipartimento di Medicina Sperimentale, Università di Genova, via de Toni 14, 16132 Genoa, Italy
  • c Department of Biochemistry, University of Pavia, via Taramelli 3b, 27100 Pavia, Italy
  • d Biotechnology Research Laboratories, IRCCS Fondazione Policlinico San Matteo, Viale Golgi 2, 27100 Pavia, Italy
  • e Divisione di Nefrologia, Spedali Civili, Piazza Spedali Civili 1, 25123 Brescia, Italy
  • 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.
    Keywords:apoA-I, apolipoprotein A-I   HDL, high-density lipoproteins   IFLM, immuno-fluorescent light microscopy   ER, endoplasmic reticulum
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