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

• 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
• DOI: 10.1038/s41467-017-00111-8

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.