title: 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.affiliation: Departments of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, UT 84132, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baehr
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Fu
mesh_terms: D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D055358:Cone Opsins / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000473:pathology; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D012174:Retinitis Pigmentosa / Q000209:etiology; D012243:Rhodopsin; D013997:Time Factors
chemical_list: D055358:Cone Opsins; D012243:Rhodopsin; D000217:Acyltransferases; C056942:lecithin-retinol acyltransferase