Chemical chaperone TUDCA preserves cone photoreceptors in a mouse model of Leber congenital amaurosis

PURPOSE. Mutations in either retinoid isomerase (RPE65) or lecithin-retinol acyltransferase (LRAT) lead to Leber congenital amaurosis (LCA). By using the Lrat ^-/- mouse model, previous studies have shown that the rapid cone degeneration in LCA was caused by endoplasmic reticulum (ER) stress induced by Sopsin aggregation. The purpose of this study is to examine the efficacy of an ER chemical chaperone, tauroursodeoxycholic acid (TUDCA), in preserving cones in the Lrat ^-/- model. METHODS. Lrat ^-/- mice were systemically administered with TUDCA and vehicle (0.15 M NaHCO ₃) every 3 days from P9 to P28. Cone cell survival was determined by counting cone cells on flat-mounted retinas. The expression and subcellular localization of cone-specific proteins were analyzed by western blotting and immunohistochemistry, respectively. RESULTS. TUDCA treatment reduced ER stress and apoptosis in Lrat ^-/- retina. It significantly slowed down cone degeneration in Lrat ^-/- mice, resulting in a ~3increase in cone density in the ventral and central retina as compared with the vehicletreated mice at P28. Furthermore, TUDCA promoted the degradation of cone membrane-associated proteins by enhancing the ER-associated protein degradation pathway. CONCLUSIONS. Systemic injection of TUDCA is effective in reducing ER stress, preventing apoptosis, and preserving cones in Lrat ^-/- mice. TUDCA has the potential to lead to the development of a new class of therapeutic drugs for treating LCA.