scholarly journals The splicing regulator Prp31 prevents retinal degeneration in Drosophila by regulating Rhodopsin levels

2018 ◽  
Author(s):  
Malte Lehmann ◽  
Sarita Hebbar ◽  
Behrens Sarah ◽  
Weihua Leng ◽  
Michaela Yuan ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Human Disease ◽  
Dietary Intervention ◽  
Phenotypic Variability ◽  
Light Stress ◽  
Splicing Factor ◽  
Phenotypic Traits ◽  
Induced Mutations ◽  
Eye Color

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, but the molecular consequences that link defects in splicing factor genes to the aetiology of the disease remain to be elucidated. Mutations in PRPF31, one of the splicing factors, are linked to RP11. To get insight into the mechanisms by which mutations in this gene lead to retinal degeneration, we induced mutations in the Drosophila orthologue Prp31. 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. Prp31 mutant flies show a high degree of phenotypic variability, similar as reported for human RP11 patients. Degeneration is associated with increased accumulation of rhodopsin 1, both in the rhabdomere and in the cell body. In fact, reducing rhodopsin levels by raising animals in a carotenoid-free medium not only suppressed rhodopsin accumulation, but also retinal degeneration. In addition, our results underscore the relevance of eye color mutations on phenotypic traits, in particular whilst studying a complex process such as retinal degeneration.Article SummaryRetinitis pigmentosa (RP) is a human disease affecting 1.6 million people worldwide. So far >50 genes have been identified that are causally related to RP. Mutations in the splicing factor PRPF31 are linked to RP11. We induced mutations in the Drosophila orthologue Prp31 and show that flies heterozygous for Prp31 undergo light-dependent retinal degeneration. Degeneration is associated with increased accumulation of the light-sensitive molecule, rhodopsin 1. In fact, reducing rhodopsin levels by dietary intervention suppressed retinal degeneration. We believe that this model will help to better understand the aetiology of the human disease.

scholarly journals Mutations in the Drosophila splicing regulator Prp31 as a model for Retinitis pigmentosa 11

2017 ◽  
Author(s):  
Malte Lehmann ◽  
Sarita Hebbar ◽  
Holger Brandl ◽  
Weihua Leng ◽  
Naharajan Lakshmanaperumal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vitamin A ◽  
Retinitis Pigmentosa ◽  
Human Disease ◽  
Splicing Factor ◽  
Induced Mutations ◽  
Cell Degeneration ◽  
Vitamin A Metabolism ◽  
Oxidation Reduction ◽  
Splicing Regulator

AbstractRetinitis pigmentosa is a clinically heterogeneous disease affecting 1.6 million people worldwide. A growing number of identified disease-causing genes are associated with the spliceosome, but the molecular consequences that link defects in splicing factor genes to the aetiology of the disease remain to be elucidated. In this paper, we present a Drosophila model for Retinitis pigmentosa 11, a human disease caused by mutations in the splicing factor PRPF31. Here, we induced mutations in the Drosophila orthologue Prp31. Mutant flies are viable and show a normal eye phenotype when kept under regular light conditions. However, when exposed to constant light, photoreceptors of mutant flies degenerate, thus resembling the human disease phenotype. Degeneration could be shown to be associated with increased oxidative stress. This increase was in agreement with severe dysregulation of genes involved in oxidation/reduction processes, as revealed by high throughput transcriptome sequencing. In fact, light induced photoreceptor cell degeneration could be attenuated by experimentally reducing oxidative stress. A comparable decrease in retinal degeneration was achieved by raising mutant larvae on a vitamin A-depleted medium, thereby reducing rhodopsin levels. Finally, transcriptome data further uncovered an overall retention of introns in mRNAs. Among those, mRNAs of genes involved in synapse assembly, growth and stability were most prominent. These results point to a multifactorial genesis of light induced degeneration in retinae of Prp31 mutant flies, including transcriptional and splicing dysregulation, oxidative stress and defects in vitamin A metabolism.

scholarly journals Mutations in the splicing regulator Prp31 lead to retinal degeneration in Drosophila

Biology Open ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. bio052332 ◽  
Author(s):  
Sarita Hebbar ◽  
Malte Lehmann ◽  
Sarah Behrens ◽  
Catrin Hälsig ◽  
Weihua Leng ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Autosomal Dominant ◽  
Light Stress ◽  
Mrna Levels ◽  
Disease Phenotype ◽  
Induced Mutations ◽  
Splicing Regulator ◽  
Splicing Machinery

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.

Gene of the month:PRPF31

2017 ◽  
Vol 70 (9) ◽  
pp. 729-732 ◽  
Author(s):  
Anna M Rose ◽  
Rong Luo ◽  
Utsav K Radia ◽  
Shomi S Bhattacharya
Keyword(s):  
Protein Structure ◽  
Retinitis Pigmentosa ◽  
Visual Impairment ◽  
Retinal Degeneration ◽  
Autosomal Dominant ◽  
Biological Function ◽  
Mrna Splicing ◽  
Splicing Factor ◽  
Eukaryotic Cells ◽  
Autosomal Dominant Retinitis Pigmentosa

Pre-mRNA splicing is an essential process in eukaryotic cells where the transcribed intronic sequences are removed, prior to translation into protein. PRPF31 is a ubiquitously expressed splicing factor, which aids in the assembly of the macromolecular spliceosome. Mutations inPRPF31cause autosomal dominant retinitis pigmentosa (adRP), a form of retinal degeneration that causes progressive visual impairment. Interestingly, mutations inPRPF31are non-penetrant, with some mutation carriers being phenotypically unaffected. In this review, the gene organisation, protein structure and biological function of PRPF31 are discussed, and the mechanisms of non-penetrance inPRPF31-associated adRP are discussed.

Retinitis pigmentosa and retinal degeneration in animals: a review

1984 ◽  
Vol 62 (6) ◽  
pp. 535-546 ◽  
Author(s):  
Yousef Matuk
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Human Disease ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Biochemical Basis ◽  
Photoreceptor Outer Segments ◽  
Rcs Rat ◽  
Retinoid Metabolism ◽  
Rcs Rats

Recent biochemical findings in the human disease, retinitis pigmentosa, and related retinal degenerative diseases in animals were reviewed and discussed. While the biochemical etiology of the human disease is not known, there are indications that retinal degeneration in the rd mouse and the Irish Setter dog are related to a deficiency in cGMP phosphodiesterase and the accumulation of cGMP in the photoreceptor outer segments. The biochemical basis of retinal degeneration in the Royal College of Surgeons (RCS) rat does not seem to be related to a defect in the metabolism of cGMP, but there are suggestions that a defect in retinoid metabolism may be involved. The possibility that the defect in RCS rats may involve receptors on the membranes of the cells of the retinal pigment epithelium or phagocytic markers on those of the rod outer segment disks was discussed.

Whole-Genome Effects of Ethyl Methanesulfonate-Induced Mutation on Nine Quantitative Traits in Outbred Drosophila melanogaster

Genetics ◽  
2001 ◽  
Vol 157 (3) ◽  
pp. 1257-1265 ◽  
Author(s):  
Hsiao-Pei Yang ◽  
Ana Y Tanikawa ◽  
Wayne A Van Voorhies ◽  
Joana C Silva ◽  
Alexey S Kondrashov
Keyword(s):  
Drosophila Melanogaster ◽  
Quantitative Traits ◽  
Spontaneous Mutation ◽  
Developmental Time ◽  
Ethyl Methanesulfonate ◽  
Induced Mutations ◽  
Mean Values ◽  
Eye Color ◽  
Recessive Mutations ◽  
The Mean

Abstract We induced mutations in Drosophila melanogaster males by treating them with 21.2 mm ethyl methanesulfonate (EMS). Nine quantitative traits (developmental time, viability, fecundity, longevity, metabolic rate, motility, body weight, and abdominal and sternopleural bristle numbers) were measured in outbred heterozygous F3 (viability) or F2 (all other traits) offspring from the treated males. The mean values of the first four traits, which are all directly related to the life history, were substantially affected by EMS mutagenesis: the developmental time increased while viability, fecundity, and longevity declined. In contrast, the mean values of the other five traits were not significantly affected. Rates of recessive X-linked lethals and of recessive mutations at several loci affecting eye color imply that our EMS treatment was equivalent to ∼100 generations of spontaneous mutation. If so, our data imply that one generation of spontaneous mutation increases the developmental time by 0.09% at 20° and by 0.04% at 25°, and reduces viability under harsh conditions, fecundity, and longevity by 1.35, 0.21, and 0.08%, respectively. Comparison of flies with none, one, and two grandfathers (or greatgrandfathers, in the case of viability) treated with EMS did not reveal any significant epistasis among the induced mutations.

Short-term high-fat feeding exacerbates degeneration in retinitis pigmentosa by promoting retinal oxidative stress and inflammation

2021 ◽  
Vol 118 (43) ◽  
pp. e2100566118
Author(s):  
Oksana Kutsyr ◽  
Agustina Noailles ◽  
Natalia Martínez-Gil ◽  
Lucía Maestre-Carballa ◽  
Manuel Martinez-Garcia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Gut Microbiome ◽  
Cell Activation ◽  
High Fat ◽  
Short Term ◽  
Oxidative Markers ◽  
Degenerative Disorders ◽  
Inflammatory State

A high-fat diet (HFD) can induce hyperglycemia and metabolic syndromes that, in turn, can trigger visual impairment. To evaluate the acute effects of HFD feeding on retinal degeneration, we assessed retinal function and morphology, inflammatory state, oxidative stress, and gut microbiome in dystrophic retinal degeneration 10 (rd10) mice, a model of retinitis pigmentosa, fed an HFD for 2 to 3 wk. Short-term HFD feeding impaired retinal responsiveness and visual acuity and enhanced photoreceptor degeneration, microglial cell activation, and Müller cell gliosis. HFD consumption also triggered the expression of inflammatory and oxidative markers in rd10 retinas. Finally, an HFD caused gut microbiome dysbiosis, increasing the abundance of potentially proinflammatory bacteria. Thus, HFD feeding drives the pathological processes of retinal degeneration by promoting oxidative stress and activating inflammatory-related pathways. Our findings suggest that consumption of an HFD could accelerate the progression of the disease in patients with retinal degenerative disorders.

scholarly journals An LED-based multi-actinic illumination system for the high throughput study of photosynthetic light responses

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5589
Author(s):  
João Serôdio ◽  
William Schmidt ◽  
Jörg C. Frommlet ◽  
Gregor Christa ◽  
Matthew R. Nitschke
Keyword(s):  
Chlorophyll Fluorescence ◽  
High Throughput ◽  
Light Stress ◽  
Limiting Factor ◽  
Phenotypic Traits ◽  
Light Responses ◽  
Illumination System ◽  
Digital Manipulation ◽  
Multiple Samples

The responses of photosynthetic organisms to light stress are of interest for both fundamental and applied research. Functional traits related to the photoinhibition, the light-induced loss of photosynthetic efficiency, are particularly interesting as this process is a key limiting factor of photosynthetic productivity in algae and plants. The quantitative characterization of light responses is often time-consuming and calls for cost-effective high throughput approaches that enable the fast screening of multiple samples. Here we present a novel illumination system based on the concept of ‘multi-actinic imaging’ of in vivo chlorophyll fluorescence. The system is based on the combination of an array of individually addressable low power RGBW LEDs and custom-designed well plates, allowing for the independent illumination of 64 samples through the digital manipulation of both exposure duration and light intensity. The illumination system is inexpensive and easily fabricated, based on open source electronics, off-the-shelf components, and 3D-printed parts, and is optimized for imaging of chlorophyll fluorescence. The high-throughput potential of the system is illustrated by assessing the functional diversity in light responses of marine macroalgal species, through the fast and simultaneous determination of kinetic parameters characterizing the response to light stress of multiple samples. Although the presented illumination system was primarily designed for the measurement of phenotypic traits related to photosynthetic activity and photoinhibition, it can be potentially used for a number of alternative applications, including the measurement of chloroplast phototaxis and action spectra, or as the basis for microphotobioreactors.

scholarly journals Microglia dynamics in retinitis pigmentosa model: formation of fundus whitening and autofluorescence as an indicator of activity of retinal degeneration

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kenichi Makabe ◽  
Sunao Sugita ◽  
Michiko Mandai ◽  
Yoko Futatsugi ◽  
Masayo Takahashi
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Outer Nuclear Layer ◽  
Fundus Autofluorescence ◽  
Fundus Photography ◽  
Photoreceptor Outer Segments ◽  
Diagnostic Interpretation ◽  
Model Formation ◽  
Thinning Rate

Abstract In patients with retinitis pigmentosa (RP), color fundus photography and fundus autofluorescence (FAF) have been used to estimate the disease progression. To understand the origin and the diagnostic interpretation of the fundus color and FAF, we performed in vivo imaging of fundus color and FAF together with histological analyses of the retinal degeneration process using the RP model mice, rd10. FAF partly represented the accumulation of microglia in the photoreceptor outer segments. Fundus whitening suggested the presence of apoptotic cells, which spatiotemporally preceded increase in FAF. We observed two patterns of FAF localization, arcuate and diffuse, each indicating different pattern of apoptosis, wavy and diffuse, respectively. Diffuse pattern of apoptosis was suppressed in dark-raised rd10 mice, in which outer nuclear layer (ONL) loss was significantly suppressed. The occupancy of FAF correlated with the thinning rate of the ONL. Fractalkine, a microglia chemotactic factor, was detected in apoptotic photoreceptors, suggesting chemokine-induced recruitment of microglia into the ONL, which paralleled with accelerated ONL loss and increased FAF occupancy. Thus, we propose that the degree of photoreceptor apoptosis and the rate of ONL thinning in RP patients might be read from the fundus color and the FAF.

scholarly journals ATF6 is required for efficient rhodopsin clearance and retinal homeostasis in the P23H rho retinitis pigmentosa mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Eun-Jin Lee ◽  
Priscilla Chan ◽  
Leon Chea ◽  
Kyle Kim ◽  
Randal J. Kaufman ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Mrna Levels ◽  
Photoreceptor Layer ◽  
Protein Levels ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractRetinitis Pigmentosa (RP) is a blinding disease that arises from loss of rods and subsequently cones. The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that mirrors RP phenotype in patients carrying the orthologous variant. Previously, we found that the P23H rhodopsin protein was degraded in P23H-KI retinas, and the Unfolded Protein Response (UPR) promoted P23H rhodopsin degradation in heterologous cells in vitro. Here, we investigated the role of a UPR regulator gene, activating transcription factor 6 (Atf6), in rhodopsin protein homeostasis in heterozygous P23H rhodopsin (Rho+/P23H) mice. Significantly increased rhodopsin protein levels were found in Atf6−/−Rho+/P23H retinas compared to Atf6+/−Rho+/P23H retinas at early ages (~ P12), while rhodopsin mRNA levels were not different. The IRE1 pathway of the UPR was hyper-activated in young Atf6−/−Rho+/P23H retinas, and photoreceptor layer thickness was unchanged at this early age in Rho+/P23H mice lacking Atf6. By contrast, older Atf6−/−Rho+/P23H mice developed significantly increased retinal degeneration in comparison to Atf6+/−Rho+/P23H mice in all retinal layers, accompanied by reduced rhodopsin protein levels. Our findings demonstrate that Atf6 is required for efficient clearance of rhodopsin protein in rod photoreceptors expressing P23H rhodopsin, and that loss of Atf6 ultimately accelerates retinal degeneration in P23H-KI mice.

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