Selective Ablation of Dehydrodolichyl Diphosphate Synthase in Murine Retinal Pigment Epithelium (RPE) Causes RPE Atrophy and Retinal Degeneration

Autor:	Timothy W. Kraft, Sriganesh Ramachandra Rao, Steven J. Fliesler, Steven J. Pittler, Stephanie J. Davis, Delores A. Stacks, Marci L DeRamus, Cyril Nii Amankwah Nyankerh
Rok vydání:	2020
Předmět:	0301 basic medicine Retinal degeneration Cre-Lox technology Cell type RPE transmigration Retinal Pigment Epithelium Biology retinal pigment epithelium dystrophy Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine retinitis pigmentosa Retinitis pigmentosa medicine Electroretinography Animals mouse models lcsh:QH301-705.5 Night Vision Mice Knockout Retina Retinal pigment epithelium Alkyl and Aryl Transferases medicine.diagnostic_test Color Vision Integrases Retinal Degeneration Reproducibility of Results Retinal General Medicine medicine.disease eye diseases Cell biology Dehydrodolichyl diphosphate synthase Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Phenotype lcsh:Biology (General) chemistry sense organs Atrophy 030217 neurology & neurosurgery Tomography Optical Coherence Photoreceptor Cells Vertebrate
Zdroj:	Cells Volume 9 Issue 3 Cells, Vol 9, Iss 3, p 771 (2020)
ISSN:	2073-4409
Popis:	Patients with certain defects in the dehydrodolichyl diphosphate synthase (DHDDS) gene (RP59 OMIM #613861) exhibit classic symptoms of retinitis pigmentosa, as well as macular changes, suggestive of retinal pigment epithelium (RPE) involvement. The DHDDS enzyme is ubiquitously required for several pathways of protein glycosylation. We wish to understand the basis for selective ocular pathology associated with certain DHDDS mutations and the contribution of specific ocular cell types to the pathology of mutant Dhdds-mediated retinal degeneration. To circumvent embryonic lethality associated with Dhdds knockout, we generated a Cre-dependent knockout allele of murine Dhdds (Dhddsflx/flx). We used targeted Cre expression to study the importance of the enzyme in the RPE. Structural alterations of the RPE and retina including reduction in outer retinal thickness, cell layer disruption, and increased RPE hyper-reflectivity were apparent at one postnatal month. At three months, RPE and photoreceptor disruption was observed non-uniformly across the retina as well as RPE transmigration into the photoreceptor layer, external limiting membrane descent towards the RPE, and patchy loss of photoreceptors. Functional loss measured by electroretinography was consistent with structural loss showing scotopic a- and b-wave reductions of 83% and 77%, respectively, at three months. These results indicate that RPE dysfunction contributes to DHDDS mutation-mediated pathology and suggests a more complicated disease mechanism than simply disruption of glycosylation.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9d7391af164abc63e444ad84cb89052a https://pubmed.ncbi.nlm.nih.gov/32245241 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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