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

Abstract

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 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: Tao Zhang, Wolfgang Baehr, Yingbin Fu
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 53 Issue 7 Pg. 3349-56 (Jun 05 2012) ISSN: 1552-5783 [Electronic] United States
• PMID: 22531707 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Cone Opsins
• Taurochenodeoxycholic Acid
• ursodoxicoltaurine

Topics

• Animals
• Antiviral Agents (administration & dosage)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Count
• Cell Survival (drug effects)
• Cone Opsins (drug effects, metabolism)
• Disease Models, Animal
• Electroretinography
• Endoplasmic Reticulum (drug effects, metabolism)
• Immunohistochemistry
• Injections, Subcutaneous
• Isomerism
• Leber Congenital Amaurosis (drug therapy, metabolism)
• Mice
• Mice, Inbred BALB C
• Retinal Cone Photoreceptor Cells (drug effects, metabolism, pathology)
• Taurochenodeoxycholic Acid (administration & dosage)