| First Author | Mockel A | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 44 | Pages | 37483-94 |
| PubMed ID | 22869374 | Mgi Jnum | J:191588 |
| Mgi Id | MGI:5462139 | Doi | 10.1074/jbc.M112.386821 |
| Citation | Mockel A, et al. (2012) Pharmacological modulation of the retinal unfolded protein response in Bardet-Biedl syndrome reduces apoptosis and preserves light detection ability. J Biol Chem 287(44):37483-94 |
| abstractText | 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. |
