Molecular genetics of retinal degeneration: A Drosophila perspective

Abstract

Inherited retinal degeneration in Drosophila has been explored for insights into similar processes in humans. Based on the mechanisms, I divide these mutations in Drosophila into three classes. The first consists of genes that control the specialization of photoreceptor cells including the morphogenesis of visual organelles (rhabdomeres) that house the visual signaling proteins. The second class contains genes that regulate the activity or level of the major rhodopsin, Rh1, which is the light sensor and also provides a structural role for the maintenance of rhabdomeres. Some mutations in Rh1 (NinaE) are dominant due to constitutive activity or folding defects, like autosomal dominant retinitis pigmentosa (ADRP) in humans. The third class consists of genes that control the Ca ( 2+) influx directly or indirectly by promoting the turnover of the second messenger and regeneration of PIP 2, or mediate the Ca ( 2+) -dependent regulation of the visual response. These gene products are critical for the increase in cytosolic Ca ( 2+ ) following light stimulation to initiate negative regulatory events. Here I will focus on the signaling mechanisms underlying the degeneration in norpA, and in ADRP-type NinaE mutants that produce misfolded Rh1. Accumulation of misfolded Rh1 in the ER triggers the unfolded protein response (UPR), while endosomal accumulation of activated Rh1 may initiate autophagy in norpA. Both autophagy and the UPR are beneficial for relieving defective endosomal trafficking and the ER stress, respectively. However, when photoreceptors fail to cope with the persistence of these stresses, a cell death program is activated leading to retinal degeneration.

Figure 1

Structure of the compound eye in Drosophila. (A) Each compound eye consists of 600–800 unit eyes (ommatidia). (B) Each ommatidium contains eight photoreceptors, R1–R8. Shown is a cross section of the distal region of an ommatidium, which reveals the R1–R7 photoreceptors with the stereotypical arrangement of rhabdomeres. Rhabdomere is the visual organelle in photoreceptor cells, and consists of densely packed membranes supported by the actin cytoskeleton (C and D). Shown is the rhabdomere of the R1–R6 photoreceptors revealed by epifluorescence of actin tagged with the green fluorescent protein (C). (D) A diagrammatic depiction of a photoreceptor cell (cross section).

Figure 2

Visual signaling in Drosophila. Light stimulation results in depolarization of Drosophila photoreceptors, as activated rhodopsin (Rho*) couples to Gq leading to the activation of PLCβ (NORPA), and the eventual opening of the TRP and TRPL channels. The INAD complex, highlighted in yellow, consists of INAD, eye-PKC, NORPA and TRP. The Ca²⁺-dependent regulatory events employ CaMKII, RDGC and eye-PKC partly to regulate Arr2, rhodopsin and TRP for the deactivation of the visual response.

Figure 3

Retinal degeneration contributed by defective trafficking of Rh1 in NinaE and norpA photoreceptors. Shown is a diagram depicting trafficking of newly translated Rh1 rhodopsin (black arrows) and of internalized photoactivated Rh1 rhodopsin (red arrows) in photoreceptors. Rh1 opsin is translated, and undergoes glycosylation and maturation in the rough ER. Mature opsin is conjugated with 11-cis 3-hydroxy-retinal to become rhodopsin, which is transported through the Golgi for its delivery to the rhabdomere. In NinaE heterozygotes, folding deficient Rh1 may form oligomeric complexes with wild-type Rh1 affecting the transport of wild-type Rh1, and resulting in degeneration of photoreceptors. In norpA photoreceptors, photoactivated Rh1 becomes rapidly internalized. However, the endosome to lysosome trafficking of endocytosed Rh1 becomes a rate-limiting step leading to accumulation of activated Rh1 in the late endosome, which leads to death of photoreceptor cells. MVB, multivesicular body.