Pharmacological Modulation of the Retinal Unfolded Protein Response in Bardet-Biedl Syndrome Reduces Apoptosis and Preserves Light Detection Ability*
- Anais Mockel‡,
- Cathy Obringer‡,
- Theodorus B. M. Hakvoort§,
- Mathias Seeliger¶,
- Wouter H. Lamers§,
- Corinne Stoetzel¶,
- Hélène Dollfus‡‖ and
- Vincent Marion‡,1
- From the ‡Laboratoire de Physiopathologie des Syndromes Rares Héréditaires, AVENIR-INSERM, EA3949, Université de Strasbourg, 67085 Strasbourg, France,
- the §Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, 1100 DD, Amsterdam, The Netherlands,
- the ¶Division of Ocular Neurodegeneration, Center for Ophthalmology, Institute for Ophthalmic Research, D-72076 Tübingen, Germany, and
- the ‖Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, 67200 Strasbourg, France
- ↵1 To whom correspondence should be addressed: National Institute for Health and Medical Research (INSERM), Laboratoire de Physiopathologie des Syndromes Rares Héréditaires, University of Strasbourg, Faculty of Medicine, 9th Floor, Bldg. 3, 11 Rue Humann, 67085 Strasbourg cedex, France. Tel: 33-3-68-85-33-34; Fax: 33-3-68-85-31-10; E-mail: vincent.marion{at}unistra.fr.
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.
- Cilia
- Endoplasmic Reticulum Stress
- Photoreceptors
- Retinal Degeneration
- Unfolded Protein Response
- Bardet-Biedl Syndrome
- Ciliopathy
- Pharmacological Treatment
Footnotes
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↵* This work was supported by the Agence Nationale pour la Recherche (ANR Call for Rare Diseases 2009) and the INSERM Avenir Program.
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This article contains supplemental text and Figs. S1–S14.
- Received June 1, 2012.
- Revision received July 24, 2012.
- © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.
