title: Chemical chaperone TUDCA preserves cone photoreceptors in a mouse model of Leber congenital amaurosis.
abstract: OBJECTIVE
  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 S-opsin 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 ∼3-fold increase in cone density in the ventral and central retina as compared with the vehicle-treated 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.
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Fu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D055358:Cone Opsins / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004596:Electroretinography; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D007279:Injections, Subcutaneous; D007536:Isomerism; D057130:Leber Congenital Amaurosis / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage*
chemical_list: D000998:Antiviral Agents; D055358:Cone Opsins; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine