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标题：Retinal Degeneration Caused by Rod-Specific Dhdds Ablation Occurs without Concomitant Inhibition of Protein N-Glycosylation
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作者：Sriganesh Ramachandra Rao ; Lara A. Skelton ; Fuguo Wu 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：6
页码：1-45
DOI：10.1016/j.isci.2020.101198
语种：English
出版社：Elsevier
摘要：SummaryDehydrodolichyl diphosphate synthase (DHDDS) catalyzes the committed step in dolichol synthesis. Recessive mutations inDHDDScause retinitis pigmentosa (RP59), resulting in blindness. We hypothesized that rod photoreceptor-specific ablation ofDhddswould cause retinal degeneration due to diminished dolichol-dependent proteinN-glycosylation.Dhddsflx/flxmice were crossed with rod-specific Cre recombinase-expressing (Rho-iCre75) mice to generate rod-specificDhddsknockout mice (Dhddsflx/flxiCre+).In vivomorphological and electrophysiological evaluation ofDhddsflx/flxiCre+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 inDhddsflx/flxiCre+mice, relative to controls; despite this,N-glycosylation of retinal proteins, including opsin (the dominant rod-specific glycoprotein), persisted inDhddsflx/flxiCre+mice. These findings challenge the conventional mechanistic view of RP59 as a congenital disorder of glycosylation.Graphical AbstractDisplay OmittedHighlights•Deletion ofDhddsin rod cells caused rapid retinal degeneration in mice•Retinal dolichol levels markedly decreased before onset of degeneration•ProteinN-glycosylation was uncompromised despiteDhddsdeletion•Degeneration also involved gliosis, microglial activation, and phagoptosisGenetics; Cell Biology