Pathophysilogical mechanism and treatment strategies for Leber congenital amaurosis.

Abstract

Mutations in retinoid isomerase, 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. We found that mislocalized M-opsin was degraded whereas mislocalized S-opsin accumulated in Lrat (-/-) cones before the onset of massive ventral/central cone degeneration. Since the ventral and central retina expresses 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 LCA patients. The aggregation of short-wavelength opsins likely caused rapid cone degenerations through an ER stress pathway as demonstrated in both the Lrat (-/-) retina and transfected cells. Based on this mechanism, we designed a new therapy of LCA by reducing ER stress. We found that systemic injection of an ER chemical chaperone, tauroursodeoxycholic acid (TUDCA), is effective in reducing ER stress, preventing apoptosis, and preserving cones in Lrat (-/-) mice.

• Authors: Yingbin Fu, Tao Zhang
• Journal: Advances in experimental medicine and biology (Adv Exp Med Biol) Vol. 801 Pg. 791-6 ( 2014) ISSN: 0065-2598 [Print] United States
• PMID: 24664772 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cholagogues and Choleretics
• Opsins
• Rod Opsins
• long-wavelength opsin
• middle-wavelength opsin
• short-wavelength opsin
• Taurochenodeoxycholic Acid
• ursodoxicoltaurine
• Acyltransferases
• lecithin-retinol acyltransferase
• retinoid isomerohydrolase
• cis-trans-Isomerases

Topics

• Acyltransferases (genetics)
• Animals
• Cholagogues and Choleretics (pharmacology)
• Disease Models, Animal
• Endoplasmic Reticulum Stress (drug effects, physiology)
• Humans
• Leber Congenital Amaurosis (drug therapy, genetics, physiopathology)
• Light
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Opsins (metabolism)
• Retinal Cone Photoreceptor Cells (drug effects, pathology, physiology)
• Rod Opsins (metabolism)
• Taurochenodeoxycholic Acid (pharmacology)
• cis-trans-Isomerases (genetics)