Gelsolin dysfunction causes photoreceptor loss in induced pluripotent cell and animal retinitis pigmentosa models

Mutations in the Retinitis Pigmentosa GTPase Regulator ( RPGR ) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human indu...

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Bibliographic Details
Published in:Nature communications Vol. 8; no. 1; pp. 271 - 10
Main Authors: Megaw, Roly, Abu-Arafeh, Hashem, Jungnickel, Melissa, Mellough, Carla, Gurniak, Christine, Witke, Walter, Zhang, Wei, Khanna, Hemant, Mill, Pleasantine, Dhillon, Baljean, Wright, Alan F., Lako, Majlinda, ffrench-Constant, Charles
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 16.08.2017
Nature Publishing Group
Nature Portfolio
Subjects:
692/308/1426
692/699/3161/3175
Actin
Actins - metabolism
Animal models
Animals
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cilia - metabolism
Disease Models, Animal
Dystrophy
Eye Proteins - genetics
Eye Proteins - metabolism
Gelsolin
Gelsolin - genetics
Gelsolin - metabolism
Guanosine triphosphatases
Humanities and Social Sciences
Humans
Induced Pluripotent Stem Cells
Mice
Mice, Knockout
multidisciplinary
Mutation
Photoreceptor Cells, Vertebrate - metabolism
Photoreceptors
Pluripotency
Protein Transport
Retina
Retinal degeneration
Retinitis pigmentosa
Retinitis Pigmentosa - genetics
Retinitis Pigmentosa - metabolism
Rhodopsin
Rhodopsin - metabolism
Science
Science (multidisciplinary)
Stem cell transplantation
Stem cells
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Mutations in the Retinitis Pigmentosa GTPase Regulator ( RPGR ) cause X-linked RP (XLRP), an untreatable, inherited retinal dystrophy that leads to premature blindness. RPGR localises to the photoreceptor connecting cilium where its function remains unknown. Here we show, using murine and human induced pluripotent stem cell models, that RPGR interacts with and activates the actin-severing protein gelsolin, and that gelsolin regulates actin disassembly in the connecting cilium, thus facilitating rhodopsin transport to photoreceptor outer segments. Disease-causing RPGR mutations perturb this RPGR-gelsolin interaction, compromising gelsolin activation. Both RPGR and Gelsolin knockout mice show abnormalities of actin polymerisation and mislocalisation of rhodopsin in photoreceptors. These findings reveal a clinically-significant role for RPGR in the activation of gelsolin, without which abnormalities in actin polymerisation in the photoreceptor connecting cilia cause rhodopsin mislocalisation and eventual retinal degeneration in XLRP. Mutations in the Retinitis Pigmentosa GTPase Regulator ( RPGR ) cause retinal dystrophy, but how this arises at a molecular level is unclear. Here, the authors show in induced pluripotent stem cells and mouse knockouts that RPGR mediates actin dynamics in photoreceptors via the actin-severing protein, gelsolin.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-017-00111-8