title: Rescuing Trafficking Mutants of the ATP-binding Cassette Protein, ABCA4, with Small Molecule Correctors as a Treatment for Stargardt Eye Disease.
abstract: Stargardt disease is the most common form of early onset macular degeneration. Mutations in ABCA4, a member of the ATP-binding cassette (ABC) family, are associated with Stargardt disease. Here, we have examined two disease-causing mutations in the NBD1 region of ABCA4, R1108C, and R1129C, which occur within regions of high similarity with CFTR, another ABC transporter gene, which is associated with cystic fibrosis. We show that R1108C and R1129C are both temperature-sensitive processing mutants that engage the cellular quality control mechanism and show a strong interaction with the chaperone Hsp 27. Both mutant proteins also interact with HDCAC6 and are degraded in the aggresome. We also demonstrate that novel corrector compounds that are being tested as treatment for cystic fibrosis, such as VX-809, can rescue the processing of the ABCA4 mutants, particularly their expression at the cell surface, and can reduce their binding to HDAC6. Thus, our data suggest that VX-809 can potentially be developed as a new therapy for Stargardt disease, for which there is currently no treatment.
authors.affiliation: From the Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, Physiology Center for Retinal Biology, and.
authors.forename: Inna
authors.initials: I
authors.lastname: Sabirzhanova
authors.affiliation: From the Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, Physiology Center for Retinal Biology, and.
authors.forename: Miquéias
authors.initials: M
authors.lastname: Lopes Pacheco
authors.affiliation: From the Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, Physiology Center for Retinal Biology, and.
authors.forename: Daniele
authors.initials: D
authors.lastname: Rapino
authors.affiliation: From the Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, Physiology Center for Retinal Biology, and.
authors.forename: Rahul
authors.initials: R
authors.lastname: Grover
authors.affiliation: Department of Ophthalmology, Johns Hopkins University, Baltimore, Maryland 21231.
authors.forename: James T
authors.initials: JT
authors.lastname: Handa
authors.affiliation: From the Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205.
authors.forename: William B
authors.initials: WB
authors.lastname: Guggino
authors.affiliation: From the Division of Gastroenterology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, Physiology Center for Retinal Biology, and Department of Ophthalmology, Johns Hopkins University, Baltimore, Maryland 21231 lcebotaru@jhmi.edu.
authors.forename: Liudmila
authors.initials: L
authors.lastname: Cebotaru
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000631:Aminopyridines / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D018942:Macrolides / Q000494:pharmacology; D008268:Macular Degeneration / Q000151:congenital / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D020011:Protective Agents / Q000494:pharmacology*; D021381:Protein Transport; D059748:Proteolysis; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000080362:Stargardt Disease; D019076:Transgenes
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters; D000631:Aminopyridines; D000813:Anilides; D052117:Benzodioxoles; C505032:CFTR protein, human; D004791:Enzyme Inhibitors; D055551:HSP27 Heat-Shock Proteins; D006877:Hydroxamic Acids; D018942:Macrolides; D020011:Protective Agents; C474316:tubacin; C057620:bafilomycin A; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; C569105:lumacaftor
keywords: ABC transporter; aggresome; cell surface protein; chaperone; chloride channel; drug action; endoplasmic reticulum-associated protein degradation (ERAD); epithelial cell; multidrug transporter; protein degradation