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Modelling autosomal dominant optic atrophy associated with OPA1 variants in iPSC-derived retinal ganglion cells

Sladen, Paul E; Jovanovic, Katarina; Guarascio, Rosellina; Ottaviani, Daniele; Salsbury, Grace; Novoselova, Tatiana; Chapple, J Paul; ... Cheetham, Michael E; + view all (2022) Modelling autosomal dominant optic atrophy associated with OPA1 variants in iPSC-derived retinal ganglion cells. Human Molecular Genetics 10.1093/hmg/ddac128. (In press). Green open access

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Abstract

Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterised by the preferential loss of retinal ganglion cells (RGCs), resulting in optic nerve degeneration and progressive bilateral central vision loss. Over 60% of genetically confirmed DOA patients carry variants in the nuclear OPA1 gene, which encodes for a ubiquitously expressed, mitochondrial GTPase protein. OPA1 has diverse functions within the mitochondrial network, facilitating inner membrane fusion and cristae modelling, regulating mitochondrial DNA maintenance and coordinating mitochondrial bioenergetics. There are currently no licensed disease-modifying therapies for DOA and the disease mechanisms driving RGC degeneration are poorly understood. Here, we describe the generation of isogenic, heterozygous OPA1 null iPSC (OPA1+/-) through CRISPR/Cas9 gene editing of a control cell line, in conjunction with the generation of DOA patient-derived iPSC carrying OPA1 variants, namely, the c.2708_2711delTTAG variant (DOA iPSC), and previously reported missense variant iPSC line (c.1334G>A, DOA+ iPSC) and CRISPR/Cas9 corrected controls. A two-dimensional (2D) differentiation protocol was used to study the effect of OPA1 variants on iPSC-RGC differentiation and mitochondrial function. OPA1+/-, DOA and DOA+ iPSC showed no differentiation deficit compared to control iPSC lines, exhibiting comparable expression of all relevant markers at each stage of differentiation. OPA1+/- and OPA1 variant iPSC-RGCs exhibited impaired mitochondrial homeostasis, with reduced bioenergetic output and compromised mitochondrial DNA maintenance. These data highlight mitochondrial deficits associated with OPA1 dysfunction in human iPSC-RGCs, and establish a platform to study disease mechanisms that contribute to RGC loss in DOA, as well as potential therapeutic interventions.

Type: Article
Title: Modelling autosomal dominant optic atrophy associated with OPA1 variants in iPSC-derived retinal ganglion cells
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/hmg/ddac128
Publisher version: https://doi.org/10.1093/hmg/ddac128
Language: English
Additional information: © The Author(s) 2022. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
Keywords: mitochondria, blindness, homeostasis, cell lines, dna, mitochondrial, genes, guanosine triphosphate phosphohydrolases, heterozygote, membrane fusion, optic atrophy, autosomal dominant, retinal ganglion cells, optic nerve, optic nerve disorders, bioenergetics, therapeutic intervention, dead on arrival, crista ampullaris, tissue degeneration, crispr, gene editing
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10150302
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