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M.S. Eckmiller; Localization of a P21-activated Kinase at Photoreceptor Outer Segment Cytoskeletons Is Consistent with the Energy Depletion Hypothesis for Retinitis Pigmentosa . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3265.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To identify the molecular components and elucidate the function of the special cytoskeletal system that is present in amphibian and human retinas at the multiple incisures of rod outer segments (OS), because evidence suggests that disturbance of this cytoskeleton can mediate retinitis pigmentosa (RP). Methods: Photoreceptor cells and OS from retinas of Xenopus toads were treated to indirect immunofluorescence with a polyclonal antibody to X-PAK5 (a Xenopus p21-activated kinase that can bind to actin and/or microtubules) or appropriate controls, and examined by fluorescence microscopy. Results: In the OS of rods and cones, X-PAK5 immunoreactivity occurred as a continuous fluorescent streak resembling the ciliary axoneme. In rod OS, additional immunoreactivity to X-PAK5 occurred as continuous longitudinal fluorescent lines coinciding with the multiple incisures. There was no significant fluorescence in OS on control preparations. The location of specific immunoreactivity to X-PAK in amphibian OS thus coincided with the location of microtubules, which organize cytoskeletal systems that in amphibian and human retinas are somewhat different in the OS of rods and cones. Conclusions: These findings identify X-PAK5 as a novel component of the microtubule-based cytoskeletal systems in photoreceptor OS. Previous studies have shown that some components of the microtubule-based cytoskeletal systems in OS are proteins encoded by genes whose defects can cause human RP, eg., myosin VIIa, which can bind to actin and likely participates in adaptive protein translocation within photoreceptors, and RP GTPase regulator (RPGR), which in rods can bind the δ-subunit of PDE, which can modify the activation/inactivation of PDE. X-PAK5 is appropriately situated at the multiple rod OS incisures so that by binding to actin, microtubules, and/or other adjacent proteins it can participate in a massive downregulation or uncoupling of phototransduction in rods exposed to prolonged bright light. These findings are consistent with the hypothesis that the primary function of the special cytoskeletal system at the multiple OS incisures in normal rods is to prevent abnormally high expenditure of energy during prolonged bright light, and that disturbance in the function of this cytoskeletal system in abnormal rods can result in progressive intracellular depletion of energy, triggering rod apoptosis and photoreceptor cell death. These findings are thus entirely consistent with the ENERGY DEPLETION HYPOTHESIS for some forms of RP.
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