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    1. Review coordinated by Life Science Editors.

      Reviewed by: Dr. Angela Andersen, Life Science Editors

      Potential Conflicts of Interest: Dr. Mill has worked with Life Science Editors on other manuscripts.

      Background: Retinitis pigmentosa (RP) is a group of rare eye diseases that cause vision loss. Symptoms usually start in childhood, and most people eventually lose most of their sight. There is no cure for RP. Mutations in retinitis pigmentosa GTPase regulator (RPGR) cause RP and compromise the renewal of light-sensitive “disc” membranes (specialized cilia) at the outer segment of photoreceptors, resulting in the loss of these cells over time. Evidence suggests that disc formation is similar to the release of ectosomes (small extracellular vesicles) and that both rely on the actin cytoskeleton. Knockdown of RPGR in retinal pigmented epithelium cells showed stronger actin filaments and reduced cilia suggesting that it may regulate nascent photoreceptor disc formation by regulating actin-mediated membrane extension in the retina (Gakovic et al., Human Molecular Genetics, 2011). In addition, RPGR patient iPSC-retinal organoids displayed an increase in F-actin expression, consistent with abnormal actin regulation (Karam et al., J Personalized Medicine, 2022).

      Question: What function of RPGR is compromised in photoreceptors to cause RP?

      Advance: The authors generated novel Rpgr mutant mice harboring human disease-causing mutations that recapitulate human disease phenotypes: aborted membrane shedding as ectosome-like vesicles, photoreceptor death and visual loss. RPGR is located at the site of disc formation – to test if it plays a role in disc genesis, they engineered a novel reporter mouse to track outer segment turnover. Rhodopsin was tagged with the self-labelling peptide SNAP- Rhodopsin is the major protein component of outer segment discs, and so incubating RhodSNAP retinal slice cultures with SNAP fluorophores results in outer segment labelling. Perturbation of RPGR resulted in a slowed rate of disc formation, leading to shortened outer segments and increased vesicle shedding. To me, the breakthrough is in the last figure: the actin depolymerizing drug Cytochalasin D in PBS was injected intravitreally, and fixed retinas were analyzed 6 hours later by electron microscopy. Cytochalasin D treatment significantly reduced the number of shed vesicles from the base of the outer segment in Rpgr-mutant mice (they now look like wild-type).

      Significance: Nails down the disease-relevant function of RPGR and a molecular mechanism of RP in photoreceptor cells, in vivo, in mice. Pharmacological rescue not only demonstrates the importance of the mechanism to disease but also sheds light on a potential therapeutic avenue for RP.

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