Genetic deletion of S-opsin prevents rapid cone degeneration in a mouse model of Leber congenital amaurosis.

Mutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal synthesis and cause Leber congenital amaurosis (LCA), a severe hereditary blindness occurring in early childhood. The pathology is attributed to a combination of 11-cis-retinal deficiency and photoreceptor degeneration. The mistrafficking of cone membrane-associated proteins including cone opsins (M- and S-opsins), cone transducin (Gαt2), G-protein-coupled receptor kinase 1 (GRK1) and guanylate cyclase 1 (GC1) has been suggested to play a role in cone degeneration. However, their precise role in cone degeneration is unclear. Here we investigated the role of S-opsin (Opn1sw) in cone degeneration in Lrat(-) (/-), a murine model for LCA, by genetic ablation of S-opsin. We show that deletion of just one allele of S-opsin from Lrat(-) (/-) mice is sufficient to prevent the rapid cone degeneration for at least 1 month. Deletion of both alleles of S-opsin prevents cone degeneration for an extended period (at least 12 months). This genetic prevention is accompanied by a reduction of endoplasmic reticulum (ER) stress in Lrat(-) (/-) photoreceptors. Despite cone survival in Opn1sw(-/-)Lrat(-) (/-) mice, cone membrane-associated proteins (e.g. Gαt2, GRK1 and GC1) continue to have trafficking problems. Our results suggest that cone opsins are the 'culprit' linking 11-cis-retinal deficiency to cone degeneration in LCA. This result has important implications for the current gene therapy strategy that emphasizes the need for a combinatorial therapy to both improve vision and slow photoreceptor degeneration.

[1]  Yingbin Fu,et al.  A Phe‐rich region in short‐wavelength sensitive opsins is responsible for their aggregation in the absence of 11‐cis‐retinal , 2013, FEBS letters.

[2]  V. Arshavsky,et al.  Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration , 2013, Proceedings of the National Academy of Sciences.

[3]  Alexander Sumaroka,et al.  Human retinal gene therapy for Leber congenital amaurosis shows advancing retinal degeneration despite enduring visual improvement , 2013, Proceedings of the National Academy of Sciences.

[4]  M. Nakazawa,et al.  M-opsin protein degradation is inhibited by MG-132 in Rpe65−/− retinal explant culture , 2012, Molecular vision.

[5]  E. Pugh,et al.  An S-Opsin Knock-In Mouse (F81Y) Reveals a Role for the Native Ligand 11-cis-Retinal in Cone Opsin Biosynthesis , 2012, The Journal of Neuroscience.

[6]  Yingbin Fu,et al.  Chemical chaperone TUDCA preserves cone photoreceptors in a mouse model of Leber congenital amaurosis. , 2012, Investigative ophthalmology & visual science.

[7]  Z. Ahmed,et al.  Gene therapy for Leber congenital amaurosis: advances and future directions , 2012, Graefe's Archive for Clinical and Experimental Ophthalmology.

[8]  Amrita,et al.  Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice , 2011, Proceedings of the National Academy of Sciences.

[9]  Yingbin Fu,et al.  Cone opsin determines the time course of cone photoreceptor degeneration in Leber congenital amaurosis , 2011, Proceedings of the National Academy of Sciences.

[10]  Rebecca K. Chance,et al.  A mouse M-opsin monochromat: Retinal cone photoreceptors have increased M-opsin expression when S-opsin is knocked out , 2011, Vision Research.

[11]  Artur V. Cideciyan,et al.  Leber congenital amaurosis due to RPE65 mutations and its treatment with gene therapy , 2010, Progress in Retinal and Eye Research.

[12]  C. Watt,et al.  Trafficking of Membrane Proteins to Cone But Not Rod Outer Segments Is Dependent on Heterotrimeric Kinesin-II , 2009, The Journal of Neuroscience.

[13]  T. Aleman,et al.  Loss of cone photoreceptors caused by chromophore depletion is partially prevented by the artificial chromophore pro-drug, 9-cis-retinyl acetate. , 2009, Human molecular genetics.

[14]  D. Mastronarde,et al.  A Computational Framework for Ultrastructural Mapping of Neural Circuitry , 2009, PLoS biology.

[15]  B. Lorenz,et al.  A comprehensive clinical and biochemical functional study of a novel RPE65 hypomorphic mutation. , 2008, Investigative ophthalmology & visual science.

[16]  Edwin M Stone,et al.  Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics , 2008, Proceedings of the National Academy of Sciences.

[17]  W. Baehr,et al.  Rpe65-/- and Lrat-/- mice: comparable models of leber congenital amaurosis. , 2008, Investigative ophthalmology & visual science.

[18]  K. Yau,et al.  Quantal noise from human red cone pigment , 2008, Nature Neuroscience.

[19]  Nick Tyler,et al.  Effect of gene therapy on visual function in Leber's congenital amaurosis. , 2008, The New England journal of medicine.

[20]  Kathleen A. Marshall,et al.  Safety and efficacy of gene transfer for Leber's congenital amaurosis. , 2008, The New England journal of medicine.

[21]  K. Palczewski,et al.  Trafficking of Membrane-Associated Proteins to Cone Photoreceptor Outer Segments Requires the Chromophore 11-cis-Retinal , 2008, The Journal of Neuroscience.

[22]  W. Baehr,et al.  A model for transport of membrane-associated phototransduction polypeptides in rod and cone photoreceptor inner segments , 2008, Vision Research.

[23]  A. J. Roman,et al.  Human cone photoreceptor dependence on RPE65 isomerase , 2007, Proceedings of the National Academy of Sciences.

[24]  J. D. Bronson,et al.  The Function of Guanylate Cyclase 1 and Guanylate Cyclase 2 in Rod and Cone Photoreceptors* , 2007, Journal of Biological Chemistry.

[25]  Hiderou Yoshida,et al.  ER stress and diseases , 2007, The FEBS journal.

[26]  M. Seeliger,et al.  Cone opsin mislocalization in Rpe65-/- mice: a defect that can be corrected by 11-cis retinal. , 2005, Investigative ophthalmology & visual science.

[27]  Birgit Lorenz,et al.  Longitudinal and cross-sectional study of patients with early-onset severe retinal dystrophy associated with RPE65 mutations , 2005, Graefe's Archive for Clinical and Experimental Ophthalmology.

[28]  Jian-xing Ma,et al.  Downregulation of cone-specific gene expression and degeneration of cone photoreceptors in the Rpe65-/- mouse at early ages. , 2005, Investigative ophthalmology & visual science.

[29]  S. Haverkamp,et al.  Impaired opsin targeting and cone photoreceptor migration in the retina of mice lacking the cyclic nucleotide-gated channel CNGA3. , 2005, Investigative ophthalmology & visual science.

[30]  W. Hauswirth,et al.  Retinal degeneration 12 (rd12): a new, spontaneously arising mouse model for human Leber congenital amaurosis (LCA). , 2005, Molecular vision.

[31]  S. Semple-Rowland,et al.  Cone cell survival and downregulation of GCAP1 protein in the retinas of GC1 knockout mice. , 2004, Investigative ophthalmology & visual science.

[32]  John Q Trojanowski,et al.  Neurodegenerative diseases: a decade of discoveries paves the way for therapeutic breakthroughs , 2004, Nature Medicine.

[33]  R. V. Van Gelder,et al.  Lecithin-retinol Acyltransferase Is Essential for Accumulation of All-trans-Retinyl Esters in the Eye and in the Liver* , 2004, Journal of Biological Chemistry.

[34]  R. Marc,et al.  Fundamental GABAergic amacrine cell circuitries in the retina: Nested feedback, concatenated inhibition, and axosomatic synapses , 2000, The Journal of comparative neurology.

[35]  M. Antoch,et al.  The Murine Cone Photoreceptor A Single Cone Type Expresses Both S and M Opsins with Retinal Spatial Patterning , 2000, Neuron.

[36]  D. Bok,et al.  Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle , 1998, Nature Genetics.

[37]  K. Narfström,et al.  The Briard dog: a new animal model of congenital stationary night blindness. , 1989, The British journal of ophthalmology.

[38]  Yingbin Fu,et al.  Pathophysilogical mechanism and treatment strategies for Leber congenital amaurosis. , 2014, Advances in experimental medicine and biology.