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.
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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)
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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
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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)
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