Suppressing thyroid hormone signaling preserves cone photoreceptors in mouse models of retinal degeneration.

Abstract

Cone phototransduction and survival of cones in the human macula is essential for color vision and for visual acuity. Progressive cone degeneration in age-related macular degeneration, Stargardt disease, and recessive cone dystrophies is a major cause of blindness. Thyroid hormone (TH) signaling, which regulates cell proliferation, differentiation, and apoptosis, plays a central role in cone opsin expression and patterning in the retina. Here, we investigated whether TH signaling affects cone viability in inherited retinal degeneration mouse models. Retinol isomerase RPE65-deficient mice [a model of Leber congenital amaurosis (LCA) with rapid cone loss] and cone photoreceptor function loss type 1 mice (severe recessive achromatopsia) were used to determine whether suppressing TH signaling with antithyroid treatment reduces cone death. Further, cone cyclic nucleotide-gated channel B subunit-deficient mice (moderate achromatopsia) and guanylate cyclase 2e-deficient mice (LCA with slower cone loss) were used to determine whether triiodothyronine (T3) treatment (stimulating TH signaling) causes deterioration of cones. We found that cone density in retinol isomerase RPE65-deficient and cone photoreceptor function loss type 1 mice increased about sixfold following antithyroid treatment. Cone density in cone cyclic nucleotide-gated channel B subunit-deficient and guanylate cyclase 2e-deficient mice decreased about 40% following T3 treatment. The effect of TH signaling on cone viability appears to be independent of its regulation on cone opsin expression. This work demonstrates that suppressing TH signaling in retina dystrophy mouse models is protective of cones, providing insights into cone preservation and therapeutic interventions.

• Authors: Hongwei Ma, Arjun Thapa, Lynsie Morris, T Michael Redmond, Wolfgang Baehr, Xi-Qin Ding
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 9 Pg. 3602-7 (Mar 04 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24550448 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antithyroid Agents
• CNGB3 protein, mouse
• Cone Opsins
• Cyclic Nucleotide-Gated Cation Channels
• Receptors, Cell Surface
• Thyroid Hormones
• Triiodothyronine
• Methimazole
• retinoid isomerohydrolase
• Guanylate Cyclase
• Gucy2e protein, mouse
• cis-trans-Isomerases

Topics

• Animals
• Antithyroid Agents (pharmacology)
• Color Vision Defects (complications, drug therapy)
• Cone Opsins (metabolism)
• Cyclic Nucleotide-Gated Cation Channels (deficiency)
• Guanylate Cyclase (deficiency)
• Leber Congenital Amaurosis (complications, drug therapy)
• Methimazole
• Mice
• Mice, Knockout
• Receptors, Cell Surface (deficiency)
• Retinal Cone Photoreceptor Cells (drug effects, metabolism, physiology)
• Retinal Degeneration (etiology, physiopathology, prevention & control)
• Signal Transduction (physiology)
• Thyroid Hormones (metabolism)
• Triiodothyronine (pharmacology)
• cis-trans-Isomerases (deficiency)