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Retinal degeneration caused by rod-specific Dhdds ablation occurs without concomitant inhibition of protein N-glycosylation

Rao, Sriganesh Ramachandra and Skelton, Lara A. and Wu, Fuguo and Onyśk, Agnieszka and Spolnik, Grzegorz and Danikiewicz, Witold and Butler, Mark C. and Stacks, Delores A. and Surmacz, Liliana and Mu, Xiuqian and Swiezewska, Ewa and Pittler, Steven J. and Fliesler, Steven J. (2020) Retinal degeneration caused by rod-specific Dhdds ablation occurs without concomitant inhibition of protein N-glycosylation. iScience, 23 (101198). pp. 4-18.

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Abstract

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 4weeks 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.

Item Type:Article
Subjects:Q Science > QH Natural history > QH301 Biology
Divisions:Department of Lipid Biochemistry
ID Code:1892
Deposited By: Ewa Swiezewska
Deposited On:29 Jun 2020 13:44
Last Modified:29 Jun 2020 13:44

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