Abstract
X-linked choroideremia (CHM) is a disease characterized by gradual retinal degeneration caused by loss of the Rab Escort Protein, REP1. Despite partial compensation by REP2 the disease is characterized by prenylation defects in multiple members of the Rab protein family that are master regulators of membrane traffic. Remarkably, the eye is the only organ affected in CHM patients, possibly because of the huge membrane traffic burden of the post mitotic photoreceptors, which synthesise outer segments, and the adjacent retinal pigment epithelium that degrades the spent portions each day. In this study, we aimed to identify defects in membrane traffic that might lead to photoreceptor cell death in CHM. In a heterozygous null female mouse model of CHM (Chmnull/WT), degeneration of the photoreceptor layer was clearly evident from increased numbers of TUNEL positive cells compared to age matched controls, small numbers of cells exhibiting signs of mitochondrial stress and greatly increased microglial infiltration. However, most rod photoreceptors exhibited remarkably normal morphology with well-formed outer segments and no discernible accumulation of transport vesicles in the inner segment. The major evidence of membrane trafficking defects was a shortening of rod outer segments that was evident at 2 months of age but remained constant over the period during which the cells die. A decrease in rhodopsin density found in the outer segment may underlie the outer segment shortening but does not lead to rhodopsin accumulation in the inner segment. Our data argue against defects in rhodopsin transport or outer segment renewal as triggers of cell death in CHM.
Highlights
The inherited retinal degenerative diseases that are collectively known as retinitis pigmentosa (RP) affect about 1 in 4000 people and are characterized by progressive photoreceptor degeneration leading to visual loss and in some cases blindness [1]
We have generated multiple mouse models of CHM but in this manuscript have focused on heterozygous null females (Chmnull/WT) that show the maximum rate of photoreceptor degeneration, as indicated by loss of photoreceptor nuclei
Apoptosis has been extremely difficult to detect in models of CHM, most likely because of the slow rate of cell death meaning that very few cells are Photoreceptor death in choroideremia undergoing apoptosis at any one time
Summary
The inherited retinal degenerative diseases that are collectively known as retinitis pigmentosa (RP) affect about 1 in 4000 people and are characterized by progressive photoreceptor degeneration leading to visual loss and in some cases blindness [1]. Causative mutations in about 100 genes have been identified [1], it remains unclear why these lead to photoreceptor death. Some of these mutations affect traffic of components of the phototransduction. Photoreceptor death in choroideremia design, data collection and analysis, decision to publish or preparation of the manuscript
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