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Invest Ophthalmol Vis Sci. 2012 Jun 5;53(7):3349-56. doi: 10.1167/iovs.12-9851.

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

Author information

1
Department of Ophthalmology & Visual Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA.

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.

PMID:
22531707
PMCID:
PMC3385966
DOI:
10.1167/iovs.12-9851
[Indexed for MEDLINE]
Free PMC Article

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