Retinal Degeneration Caused by Rod-Specific Dhdds Ablation Occurs without Concomitant Inhibition of Protein N-Glycosylation
Sriganesh Ramachandra Rao,
Lara A. Skelton,
Fuguo Wu,
Agnieszka Onysk,
Grzegorz Spolnik,
Witold Danikiewicz,
Mark C. Butler,
Delores A. Stacks,
Liliana Surmacz,
Xiuqian Mu,
Ewa Swiezewska,
Steven J. Pittler,
Steven J. Fliesler
Affiliations
Sriganesh Ramachandra Rao
Department of Ophthalmology/Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14209, USA; Research Service, VA Western NY Healthcare System, Buffalo, NY 142015, USA; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14203, USA
Lara A. Skelton
Department of Ophthalmology/Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14209, USA; Research Service, VA Western NY Healthcare System, Buffalo, NY 142015, USA; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14203, USA
Fuguo Wu
Department of Ophthalmology/Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14209, USA; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14203, USA; New York State Center of Excellence in Bioinformatics and Life Sciences, State University of New York- University at Buffalo, Buffalo, NY 14203, USA
Agnieszka Onysk
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
Grzegorz Spolnik
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw 02106, Poland
Witold Danikiewicz
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw 02106, Poland
Mark C. Butler
Department of Ophthalmology/Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14209, USA; Research Service, VA Western NY Healthcare System, Buffalo, NY 142015, USA
Delores A. Stacks
Department of Optometry and Vision Science, Vision Science Research Center, School of Optometry, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Liliana Surmacz
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
Xiuqian Mu
Department of Ophthalmology/Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14209, USA; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14203, USA; New York State Center of Excellence in Bioinformatics and Life Sciences, State University of New York- University at Buffalo, Buffalo, NY 14203, USA
Ewa Swiezewska
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
Steven J. Pittler
Department of Optometry and Vision Science, Vision Science Research Center, School of Optometry, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Steven J. Fliesler
Department of Ophthalmology/Ross Eye Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14209, USA; Research Service, VA Western NY Healthcare System, Buffalo, NY 142015, USA; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York- University at Buffalo, Buffalo, NY 14203, USA; Corresponding author
Summary: Dehydrodolichyl diphosphate synthase (DHDDS) catalyzes the committed step in dolichol synthesis. Recessive mutations in DHDDS cause retinitis pigmentosa (RP59), resulting in blindness. We hypothesized that rod photoreceptor-specific ablation of Dhdds would cause retinal degeneration due to diminished dolichol-dependent protein N-glycosylation. Dhddsflx/flx mice were crossed with rod-specific Cre recombinase-expressing (Rho-iCre75) mice to generate rod-specific Dhdds knockout mice (Dhddsflx/flx iCre+). In vivo morphological and electrophysiological evaluation of Dhddsflx/flx iCre+ retinas revealed mild retinal dysfunction at postnatal (PN) 4 weeks, compared with age-matched controls; however, rapid photoreceptor degeneration ensued, resulting in almost complete loss of rods and cones by PN 6 weeks. Retina dolichol levels were markedly decreased by PN 4 weeks in Dhddsflx/flx iCre+ mice, relative to controls; despite this, N-glycosylation of retinal proteins, including opsin (the dominant rod-specific glycoprotein), persisted in Dhddsflx/flx iCre+ mice. These findings challenge the conventional mechanistic view of RP59 as a congenital disorder of glycosylation.
