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Gelsolin dysregulation causes photoreceptor loss in induced pluripotent stem cell and animal models of retinitis pigmentosa
Lookup NU author(s)
Dr Roly Megaw
Dr Carla Mellough
Professor Majlinda Lako
Megaw R, Abu-Arafeh H, Jungnickel M, Mellough C, Gurniak-Witke C, Witke W, Zhang W, Khanna G, Mill P, Dhillon B, Wright AF, Lako M, Ffrench-Constant C
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The rod photoreceptor enhances processing of visual stimuli by compartmentalising the proteins critical for phototransduction within its outer segment (OS). The OS emerges from the distal end of the connecting cilium (CC), with membrane extensions folding to form thousands of disc-like processes that stack to form the body of the OS. The CC is therefore a highly specialised primary cilium whose protein composition is unique to the retina. Up to 10% of OS discs are renewed every day
and, with all photoreceptor proteins being synthesised in the cell’s inner segment (IS), this high rate of OS turnover requires high levels of protein trafficking from the IS to (and across) the connecting cilium to maintain homeostasis. Indeed, up to 1000 molecules of rhodopsin are believed to be trafficked through the 0.3μm-wide connecting cilium in human photoreceptors per second
and breakdown of this cilia trafficking results in protein mislocalisation and, eventually, photoreceptor death. Such photoreceptor degeneration is the hallmark of retinitis pigmentosa (RP)
, a heterogenous group of inherited retinal dystrophies affecting 1 in 3000 people
. RP causes severe visual loss and blindness in middle age.
mutations account for 70-90% of XLRP and 10-15% of all RP.
Whilst its exact function remains unknown, RPGR localises to the base of the CC and previous work in knockout mouse models has suggested a role in trafficking of rhodopsin to the OS.
Additionally, depletion of RPGR in cell lines increases actin polymerization.
To define RPGR’s role in photoreceptor maintenance and to investigate the molecular pathogenesis of XLRP, we generated induced pluripotent stem cells (iPSCs) from patients with
type XLRP (
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