Retinal Degeneration Caused by Rod-Specific Dhdds Ablation Occurs without Concomitant Inhibition of Protein N-Glycosylation

作者：Sriganesh Ramachandra Rao, Lara A. Skelton, Fuguo Wu, Agnieszka Onyśk, Grzegorz Spólnik, Witold Danikiewicz, Mark C. Butler, Delores A. Stacks, Liliana Surmacz, Xiuqian Mu, Ewa Świeżewska, Steven J. Pittler, Steven J. Fliesler · 发表于：iScience · 年份：2020 · DOI：10.1016/j.isci.2020.101198 · 被引用次数：25 · 研究领域：Retinal Development and Disorders、Cellular transport and secretion、Retinal Diseases and Treatments

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. Dhdds flx/flx mice were crossed with rod-specific Cre recombinase-expressing (Rho-iCre75) mice to generate rod-specific Dhdds knockout mice ( Dhdds flx/flx iCre + ). In vivo morphological and electrophysiological evaluation of Dhdds flx/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 Dhdds flx/flx iCre + mice, relative to controls; despite this, N -glycosylation of retinal proteins, including opsin (the dominant rod-specific glycoprotein), persisted in Dhdds flx/flx iCre + mice. These findings challenge the conventional mechanistic view of RP59 as a congenital disorder of glycosylation.