Work in Drosophila and analyses of specific mutations in human rhodopsin support a connection between high levels of light-dependent rhodopsin endocytosis and retinal degeneration. In Drosophila photoreceptors, endocytosis of a large amount of rhodopsin at a rapid rate results in cell death.
Initial work in Drosophila was done with mutations in the norpA gene, which encodes an eye-specific phospholipase C that is essential for the photoresponse. Loss-of-function mutations of norpA exhibit very high levels of rhodopsin endocytosis under light stimulation, light-dependent photoreceptor cell death, and retinal degeneration.
Data are consistent with a model that photoreceptor cell death is induced by excessive light-dependent endocytosis of rhodopsin and its subsequent accumulation in the late endosomes. Mutations in Drosophila genes impacting endocytosis and lysosomal degradation, including cm and lt, have been used to investigate this process. Loss-of-function mutations in these genes also result in high levels of rhodopsin endocytosis, light-dependent photoreceptor cell death, and retinal degeneration.
Impaired autophagy may contribute to endosomal rhodopsin accumulation. Light-dependent retinal degeneration is observed in the knockdown or mutation of autophagy-essential components such as Atg7, Atg8a, Pisd and bbc. It is postulated that activated rhodopsin is degraded by autophagy in collaboration with endosomal pathways.
It has been shown that the retromer complex is expressed in fly photoreceptors and that it is required for recycling endocytosed rhodopsin upon light stimulation. Assessed in somatic clones in the eye, loss of either retromer subunit Vps35 or Vps26 causes rhodopsin mislocalization in the photoreceptors and severe light-induced photoreceptor degeneration. The human orthologs of Dmel\Vps26, Hsap\VPS26A and Hsap\VPS26B, have been introduced into flies. Ubiquitous expression of either wild-type human gene results in heterologous rescue (functional complementation) of the lethal phenotype of a Dmel\Vps26 loss-of-function mutation; the light-dependent retinal degeneration phenotype is also rescued.
Some mutations that result in impaired mitochondrial energy production appear to causes light-induced photoreceptor degeneration that is independent of oxidative stress; mutations in the Drosophila genes Lrpprc2 (see FBhh0000353) and Pdha fall into this category. It is postulated that the observed photoreceptor degeneration is the result of excessive endocytosis of rhodopsin during light exposure.
Although features of the observed photoreceptor cell death resemble those of developmental apoptosis, evidence in flies supports involvement of a different cell-death pathway.
See also the human disease model reports 'retinal disease, rhodopsin-related' (FBhh0000219) and 'mitochondrial complex IV deficiency, nuclear type 5' (FBhh0000353). One of the retromer components, VPS35, is implicated in a form of Parkinson disease (see FBhh0000030).
[updated Apr. 2021 by FlyBase; FBrf0222196]
High-scoring ortholog of human AP3M1 and AP3M2. Dmel\cm shares 69-70% identity and 85% similarity with the human genes.
High-scoring ortholog of human VPS41. Dmel\lt shares 38% identity and 58% similarity with the human gene.
High-scoring ortholog of human VPS35 (1 Drosophila to 1 human). Dmel\Vps35 shares 61% identity and 78% similarity with the human gene.
High-scoring ortholog of human VPS26A and VPS26B (1 Drosophila to 2 human). Dmel\Vps26 shares 65-69% identity and 75-81% similarity with the human genes.
High-scoring ortholog of human PDHA1 and PDHA2 (1 Drosophila to 2 human). Dmel\Pdha shares 53-56% identity and 68-72% similarity with the human genes.
