Retinal Ganglion Cells With a Glaucoma OPTN(E50K) Mutation Exhibit Neurodegenerative Phenotypes when Derived from Three-Dimensional Retinal Organoids.

Stem Cell Reports
Kirstin B VanderWallJason S Meyer

Abstract

Retinal ganglion cells (RGCs) serve as the connection between the eye and the brain, with this connection disrupted in glaucoma. Numerous cellular mechanisms have been associated with glaucomatous neurodegeneration, and useful cellular models of glaucoma allow for the precise analysis of degenerative phenotypes. Human pluripotent stem cells (hPSCs) serve as powerful tools for studying human disease, particularly cellular mechanisms underlying neurodegeneration. Thus, efforts focused upon hPSCs with an E50K mutation in the Optineurin (OPTN) gene, a leading cause of inherited forms of glaucoma. CRISPR/Cas9 gene editing introduced the OPTN(E50K) mutation into existing lines of hPSCs, as well as generating isogenic controls from patient-derived lines. RGCs differentiated from OPTN(E50K) hPSCs exhibited numerous neurodegenerative deficits, including neurite retraction, autophagy dysfunction, apoptosis, and increased excitability. These results demonstrate the utility of OPTN(E50K) RGCs as an in vitro model of neurodegeneration, with the opportunity to develop novel therapeutic approaches for glaucoma.

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Citations

Nov 17, 2020·Frontiers in Cell and Developmental Biology·Oriane RabesandratanaGael Orieux
Nov 22, 2020·The Ocular Surface·Navid ManafiAlireza Mashaghi
Feb 15, 2021·Survey of Ophthalmology·Luciano QuarantaIvano Riva
Dec 4, 2020·Current Ophthalmology Reports·Lauren K WarehamDavid J Calkins
Dec 29, 2020·Development·Michelle O'Hara-Wright, Anai Gonzalez-Cordero
Apr 4, 2021·International Journal of Molecular Sciences·Gianluca CostamagnaStefania Corti
Nov 7, 2020·Cell Stem Cell·Delilah HendriksBenedetta Artegiani
May 25, 2021·Frontiers in Cellular Neuroscience·Anne VielleM Natalia Vergara
Jul 27, 2021·Development·Michelle O'Hara-Wright, Anai Gonzalez-Cordero
Aug 13, 2021·Translational Vision Science & Technology·Michael L RisnerDavid J Calkins

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Methods Mentioned

BETA
PCR
Flow cytometry
transfection
FACS

Software Mentioned

Photoshop
ImageJ
FastQC
DESeq2
NeuronJ
STAR RNA sequencing aligner

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