Special Article
Cell Death in Retinitis Pigmentosa: Gap Junctions and the ‘Bystander’ Effect

https://doi.org/10.1006/exer.2002.1155Get rights and content

Abstract

Retinitis pigmentosa (RP) constitutes a group of genetically mediated, degenerative retinal diseases that display a broad range of phenotypes. There is appreciable heterogeneity in the pathogenetic mechanisms that underlie the various forms of RP, but a substantial percentage of the known cases arise as a consequence of mutations in rhodopsin or other rod-specific proteins. However, despite the fact that the genetic defect is expressed solely in the rod photoreceptors, otherwise healthy cone photoreceptors invariably die, resulting in severe visual impairment. In this paper, the author proposes a mechanism that may be responsible, at least in part, for this unfortunate circumstance. The basic premise of the hypothesis is that the spread of the disease from dying rods to genetically normal cones is a form of ‘bystander’ effect, mediated by the gap junctions that exist between these photoreceptor subtypes. On this view, agents that trigger the apoptotic process permeate the intercellular gap-junctional channels to carry the disease from rods to neighboring cones. If permeation of noxious substances through gap junctions is a significant factor in the non-cell-autonomous spread of photoreceptor degeneration, blocking transmission through these channels may provide a means for therapeutic intervention. Many substances are known to block gap-junctional communication, but if the rod–cone channel is to be targeted, it will be essential to identify the connexins that form the gap junctions between the two types of photoreceptor, and to develop drugs that selectively affect their junctional properties. Clearly, passage of toxic agents through gap junctions may not be the only form of cell–cell interaction by which dying rods could cause cone cell death, and in this brief account, the author considers other avenues that are currently being explored to explain this phenomenon.

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      Because rods and cones are coupled though gap junctions, which are large enough to allow the diffusion of intracellular signaling molecules (Bennett and Zukin, 2004; Connors and Long, 2004), it has been proposed that photoreceptor metabolic coupling may play a role in photoreceptor survival and/or death. Specifically, it has been suggested that cone survival might depend on the diffusion of nutrients and protective factors from coupled healthy rods (Striedinger et al., 2005; Ma et al., 2018; Xu et al., 2022) and/or cones might die due to the diffusion of pro-apoptotic factors from coupled dying rods (Ripps, 2002). Thus, by modulating the rod/cone gap junction conductance on a daily basis, the retinal clock may play a key role in the balance between life and death of photoreceptor cells.

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    Address correspondence to: Dr Harris Ripps, Department of Ophthalmology and Visual Sciences, 1855 West Taylor Street, Chicago, IL 60612, U.S.A. E-mail: [email protected]

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