Rhodopsin homeostasis and retinal degeneration: lessons from the fly

Abstract

Rhodopsins (Rh) are G-protein-coupled receptors that function as light sensors in photoreceptors. In humans, mutations in Rhodopsins cause retinitis pigmentosa, a degenerative disease that ultimately results in blindness. Studies in Drosophila have provided many insights into basic Rhodopsin biology and identified pathways that lead to retinal degeneration. It has been shown that because Rhodopsin is very abundant in photoreceptors, its accumulation in numerous organelles induces severe stress and results in degeneration of these cells. Moreover, genetic lesions that affect proper activation of membrane-bound Rh lead to disruption in Ca2+ homeostasis which also causes photoreceptor degeneration. Here, we review the molecular signals involved in Rhodopsin homeostasis and the mechanisms underlying retinal degeneration in flies, and discuss possible links to human diseases.

The Retromer Complex Is Required for Rhodopsin Recycling and Its Loss Leads to Photoreceptor Degeneration

“…Each ommatidium contains eight PRs (R1–R8) that express rhodopsin proteins [1],[2],[21]–[23]. Rhodopsin 1 (Rh1) is the major rhodopsin that is primarily expressed in R1–R6 [1],[2],[21],[22].…”

Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration

“…They begin to degenerate several days after eclosion and the process occurs faster in sicily and Marf mutants than in Aats-met mutant clones (Figure S1E) as revealed by fluorescently conjugated phalloidin labeling of actin rich rhabdomeres. Elongated, or diffuse rhabdomeres are characteristic for mutants that cause a progressive photoreceptor degeneration (Xiong and Bellen, 2013). …”

Phospholipase D activity couples plasma membrane endocytosis with retromer dependent recycling

“…Following photon absorption, Rh1 undergoes photoisomerization to meta-rhodopsin (M). M is phosphorylated at its C-terminus, binds β-arrestin and this complex is removed from the microvillar membrane via clathrin-dependent endocytosis to be either recycled back to the microvillar plasma membrane (Wang et al, 2014) or trafficked to the lysosomes for degradation (Chinchore et al, 2009) [reviewed in (Xiong and Bellen, 2013)]. Tight regulation of this process is critical for rhabdomere integrity during illumination as mutants defective in any of the several steps of the rhodopsin cycle undergo light-dependent collapse of the rhabdomere [reviewed in (Raghu et al, 2012)].…”