Cell death in retinitis pigmentosa: gap junctions and the 'bystander' effect.
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.
Ripps
Harris
H
Lions of Illinois Eye Research Institute, Department of Ophthalmology and Visual Sciences, Chicago, IL 60612, USA. harripp@uic.edu
D017209:Apoptosis; D024201:Bystander Effect; D017630:Connexins / Q000502:physiology; D017629:Gap Junctions / Q000473:pathology*; D006801:Humans; D012174:Retinitis Pigmentosa / Q000473:pathology* / Q000503:physiopathology
D017630:Connexins