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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Vydáno v:	Nature communications Ročník 8; číslo 1; s. 271 - 10
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 16.08.2017 Nature Publishing Group Nature Portfolio
Témata:	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
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-017-00111-8