Cone opsin determines the time course of cone photoreceptor degeneration in Leber congenital amaurosis.

Abstract

Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal recycling and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early childhood. We used Lrat(-)(/-), a murine model for LCA, to investigate the mechanism of rapid cone degeneration. Although both M and S cone opsins mistrafficked as reported previously, mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat(-)(/-) cones before the onset of massive ventral/central cone degeneration. As the ventral and central retina express higher levels of S-opsin than the dorsal retina in mice, our results may explain why ventral and central cones degenerate more rapidly than dorsal cones in Rpe65(-)(/-) and Lrat(-)(/-) LCA models. In addition, human blue opsin and mouse S-opsin, but not mouse M-opsin or human red/green opsins, aggregated to form cytoplasmic inclusions in transfected cells, which may explain why blue cone function is lost earlier than red/green-cone function in patients with LCA. The aggregation of short-wavelength opsins likely caused rapid cone degenerations through an endoplasmic reticulum stress pathway, as demonstrated in both the Lrat(-)(/-) retina and transfected cells. Replacing rhodopsin with S-opsin in Lrat(-)(/-) rods resulted in mislocalization and aggregation of S-opsin in the inner segment and the synaptic region of rods, ER stress, and dramatically accelerated rod degeneration. Our results demonstrate that cone opsins play a major role in determining the degeneration rate of photoreceptors in LCA.

• Authors: Tao Zhang, Ning Zhang, Wolfgang Baehr, Yingbin Fu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 21 Pg. 8879-84 (May 24 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21555576 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cone Opsins
• Rhodopsin
• Acyltransferases
• lecithin-retinol acyltransferase

Topics

• Acyltransferases (deficiency, genetics)
• Animals
• Cone Opsins (physiology)
• Endoplasmic Reticulum (pathology)
• Humans
• Leber Congenital Amaurosis (pathology)
• Mice
• Mice, Knockout
• Protein Transport
• Retinal Cone Photoreceptor Cells (pathology)
• Retinitis Pigmentosa (etiology)
• Rhodopsin
• Time Factors