title: Pharmacological modulation of the retinal unfolded protein response in Bardet-Biedl syndrome reduces apoptosis and preserves light detection ability.
abstract: Ciliopathies, a class of rare genetic disorders, present often with retinal degeneration caused by protein transport defects between the inner segment and the outer segment of the photoreceptors. Bardet-Biedl syndrome is one such ciliopathy, genetically heterogeneous with 17 BBS genes identified to date, presenting early onset retinitis pigmentosa. By investigating BBS12-deprived retinal explants and the Bbs12(-/-) murine model, we show that the impaired intraciliary transport results in protein retention in the endoplasmic reticulum. The protein overload activates a proapoptotic unfolded protein response leading to a specific Caspase12-mediated death of the photoreceptors. Having identified a therapeutic window in the early postnatal retinal development and through optimized pharmacological modulation of the unfolded protein response, combining three specific compounds, namely valproic acid, guanabenz, and a specific Caspase12 inhibitor, achieved efficient photoreceptor protection, thereby maintaining light detection ability in vivo.
authors.affiliation: Laboratoire de Physiopathologie des Syndromes Rares Héréditaires, AVENIR-INSERM, EA3949, Université de Strasbourg, 67085 Strasbourg, France.
authors.forename: Anais
authors.initials: A
authors.lastname: Mockel
authors.forename: Cathy
authors.initials: C
authors.lastname: Obringer
authors.forename: Theodorus B M
authors.initials: TB
authors.lastname: Hakvoort
authors.forename: Mathias
authors.initials: M
authors.lastname: Seeliger
authors.forename: Wouter H
authors.initials: WH
authors.lastname: Lamers
authors.forename: Corinne
authors.initials: C
authors.lastname: Stoetzel
authors.forename: Hélène
authors.initials: H
authors.lastname: Dollfus
authors.forename: Vincent
authors.initials: V
authors.lastname: Marion
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020788:Bardet-Biedl Syndrome / Q000188:drug therapy*; D001692:Biological Transport; D053454:Caspase 12 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018833:Chaperonins / Q000172:deficiency / Q000235:genetics; D002923:Cilia / Q000378:metabolism / Q000473:pathology; D019610:Cytoprotection; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006143:Guanabenz / Q000494:pharmacology / Q000627:therapeutic use; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010786:Photoreceptor Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D056811:Unfolded Protein Response / Q000187:drug effects*; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use; D014785:Vision, Ocular / Q000187:drug effects*
chemical_list: C547664:Bbs12 protein, mouse; D061945:Caspase Inhibitors; D014635:Valproic Acid; C506440:Casp12 protein, mouse; D053454:Caspase 12; D018833:Chaperonins; D006143:Guanabenz