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

摘要

Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-c/s-retinal recycling and cause Leber congenital amaurosis (LCA), the most severe retinal dystrophy in early childhood. We used Lraf~(-1-), 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~(-1-) 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~(-1-) and Lrat~(-1-) 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 trans-fected 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~(-1-)retina and transfected cells. Replacing rhodopsin with S-opsin in Lrat~(-1-) rods resulted in mis-localization 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 photorecep-tors in LCA.