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      Pharmacological modulation of the retinal unfolded protein response in Bardet-Biedl syndrome reduces apoptosis and preserves light detection ability.

      The Journal of Biological Chemistry
      Animals, Apoptosis, drug effects, Bardet-Biedl Syndrome, drug therapy, Biological Transport, Caspase 12, metabolism, Caspase Inhibitors, pharmacology, therapeutic use, Chaperonins, deficiency, genetics, Cilia, pathology, Cytoprotection, Endoplasmic Reticulum Stress, Guanabenz, Kinetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Photoreceptor Cells, enzymology, Retina, Signal Transduction, Tissue Culture Techniques, Unfolded Protein Response, Valproic Acid, Vision, Ocular

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          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.

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