Abstract
ABSTRACTRetinitis pigmentosa (RP) is a clinically heterogeneous disease affecting 1.6 million people worldwide. The second-largest group of genes causing autosomal dominant RP in human encodes regulators of the splicing machinery. Yet, how defects in splicing factor genes are linked to the aetiology of the disease remains largely elusive. To explore possible mechanisms underlying retinal degeneration caused by mutations in regulators of the splicing machinery, we induced mutations in Drosophila Prp31, the orthologue of human PRPF31, mutations in which are associated with RP11. Flies heterozygous mutant for Prp31 are viable and develop normal eyes and retina. However, photoreceptors degenerate under light stress, thus resembling the human disease phenotype. Degeneration is associated with increased accumulation of the visual pigment rhodopsin 1 and increased mRNA levels of twinfilin, a gene associated with rhodopsin trafficking. Reducing rhodopsin levels by raising animals in a carotenoid-free medium not only attenuates rhodopsin accumulation, but also retinal degeneration. Given a similar importance of proper rhodopsin trafficking for photoreceptor homeostasis in human, results obtained in flies presented here will also contribute to further unravel molecular mechanisms underlying the human disease.This paper has an associated First Person interview with the co-first authors of the article.
Highlights
Retinitis pigmentosa (RP; OMIM 268000) is a clinically heterogeneous group of retinal dystrophies, which affects more than one million people worldwide
Two Prp31 alleles were discovered by targeting induced local lesions in genomes (TILLING) It was recently shown that RNAi-mediated knockdown of Drosophila Prp31 in the eye using eye-specific Gal4-lines [eyeless-Gal4 or GMR-Gal4] results in abnormal eye development, ranging from smaller eyes to complete absence of the eye, including loss of photoreceptor cells (PRCs) and pigment cells (Ray et al, 2010)
We aimed to establish a more meaningful Drosophila model for RP11associated retinal degeneration, a human disease associated with mutations in the human orthologue PRPF31, which would allow a deeper insight into the role of this splicing factor in the origin and progression of the disease
Summary
Retinitis pigmentosa (RP; OMIM 268000) is a clinically heterogeneous group of retinal dystrophies, which affects more than one million people worldwide. One hypothesis suggests that PRCs with only half the copy number of a gene encoding a general splicing component cannot cope with the elevated demand of RNA-/ protein synthesis required to maintain the exceptionally high metabolic rate of PRCs in comparison to other tissues. Halving their gene dose eventually results in apoptosis. This model is currently favoured, other mechanisms, such as impaired splicing of PRC-specific mRNAs or toxic effects caused by accumulation of mutant proteins have been discussed and may contribute to the disease phenotype [discussed in (Mordes et al, 2006; Scotti and Swanson, 2016; Tanackovic et al, 2011)]. More recent data obtained from retinal organoids established from RP11 patients showed that removing one copy of PRPF31 affects the splicing machinery in retinal and retinal pigment epithelial (RPE) cells, but not in patient-derived fibroblasts or iPS cells (Buskin et al, 2018)
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