Accumulation of Rhodopsin in Late Endosomes Triggers Photoreceptor Cell Degeneration

Abstract

Progressive retinal degeneration is the underlying feature of many human retinal dystrophies. Previous work using Drosophila as a model system and analysis of specific mutations in human rhodopsin have uncovered a connection between rhodopsin endocytosis and retinal degeneration. In these mutants, rhodopsin and its regulatory protein arrestin form stable complexes, and endocytosis of these complexes causes photoreceptor cell death. In this study we show that the internalized rhodopsin is not degraded in the lysosome but instead accumulates in the late endosomes. Using mutants that are defective in late endosome to lysosome trafficking, we were able to show that rhodopsin accumulates in endosomal compartments in these mutants and leads to light-dependent retinal degeneration. Moreover, we also show that in dying photoreceptors the internalized rhodopsin is not degraded but instead shows characteristics of insoluble proteins. Together these data implicate buildup of rhodopsin in the late endosomal system as a novel trigger of death of photoreceptor neurons.

TheDrosophilaSK Channel (dSK) Contributes to Photoreceptor Performance by Mediating Sensitivity Control at the First Visual Network

“…Heads of dark-reared flies of either sex were bisected, fixed, and embedded as previously described (Chinchore et al, 2009). Eye cross sections (1 m) were cut using a Sorvall ultra microtome MT-1, stained with toluidine blue and borax, and observed using a Zeiss Axioplan2 microscope.…”

Molecular genetics of retinal degeneration: A Drosophila perspective

“…These include arrestin 1 (Arr1), 55 Arr2, 45 rdgC, 41,56 sun (sunglass), 57 and the 'granule group genes'. 58 While both Arr1 and Arr2 contribute to the inactivation of Rh1, 45 Arr1 also is critical for promoting Rh1 endocytosis. 55 The internalized Rh1 can be detected in multivesicular bodies and appears targeted for degradation.…”

“…55 The internalized Rh1 can be detected in multivesicular bodies and appears targeted for degradation. 55 The 'granule group gene' products play a role in the endosome to lysosome trafficking, 58 while the sun gene encodes a novel tetraspanin that may modulate the degradation of Rh1 in the lysosome. 57 Conceivably, these class II mutations result in light-dependent retinal degeneration because activation of Rh1 is required.…”

Autophagy-Dependent Rhodopsin Degradation Prevents Retinal Degeneration inDrosophila

“…In normal photoreceptors, rhodopsin is transported through early and late endosomes and multivesicular bodies (MVBs) before delivery to lysosomes for degradation (Alloway et al, 2000;Xu et al, 2004;Acharya et al, 2008;Chinchore et al, 2009). Defects in genes involved in this lysosomal trafficking pathway, such as Sunglasses (Sun) (Xu et al, 2004), or the vacuolar protein sorting (vps) mutants, including carnation/vps33 and light/vps41 (Chinchore et al, 2009), result in retinal degeneration in Drosophila, attributable to the aberrant accumulation of rhodopsin.…”

“…Defects in genes involved in this lysosomal trafficking pathway, such as Sunglasses (Sun) (Xu et al, 2004), or the vacuolar protein sorting (vps) mutants, including carnation/vps33 and light/vps41 (Chinchore et al, 2009), result in retinal degeneration in Drosophila, attributable to the aberrant accumulation of rhodopsin. Thus, efficient rhodopsin degradation appears to be crucial for the viability of photoreceptor cells.…”