Dataset Information

A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration.

ABSTRACT: Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chinese medicines to exert prophylactic visual benefit. This SchB benefit was investigated in this study in pde6cw59, a zebrafish retinal-degeneration model. In this model, the pde6c gene (phosphodiesterase 6C, cGMP-specific, cone, alpha prime) carried a mutation which caused cone degeneration. This altered the local environment and caused the bystander rods to degenerate too. To test SchB on the pde6cw59 mutants, a treatment concentration was first determined that would not cause morphological defects, and would initiate known physiological response. Then, the mutants were treated with the optimized SchB concentration before the appearance of retinal degeneration at 3 days postfertilization (dpf). The light sensation of animals was evaluated at 6 dpf by the visual motor response (VMR), a visual startle that could be initiated by drastic light onset and offset. The results show that the VMR of pde6cw59 mutants towards light onset was enhanced by the SchB treatment, and that the initial phase of the enhancement was primarily mediated through the mutants' eyes. Further immunostaining analysis indicates that the treatment specifically reduced the size of the abnormally large rods. These observations implicate an interesting hypothesis: that the morphologically-improved rods drive the observed VMR enhancement. Together, these investigations have identified a possible visual benefit of SchB on retinal degeneration, a benefit that can potentially be further developed to extend functional vision in patients.

SUBMITTER: Zhang L

PROVIDER: S-EPMC4773124 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration.

Zhang Liyun L Xiang Lue L Liu Yiwen Y Venkatraman Prahatha P Chong Leelyn L Cho Jin J Bonilla Sylvia S Jin Zi-Bing ZB Pang Chi Pui CP Ko Kam Ming KM Ma Ping P Zhang Mingzhi M Leung Yuk Fai YF

PloS one 20160301 3

Retinal degeneration is often progressive. This feature has provided a therapeutic window for intervention that may extend functional vision in patients. Even though this approach is feasible, few promising drug candidates are available. The scarcity of new drugs has motivated research to discover novel compounds through different sources. One such example is Schisandrin B (SchB), an active component isolated from the five-flavor fruit (Fructus Schisandrae) that is postulated in traditional Chin ...[more]

PMID: 26930483

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Project description:Introduction: Pathogenic mutations in RPGR ORF15, one of two major human RPGR isoforms, were responsible for most X-linked retinitis pigmentosa cases. Previous studies have shown that RPGR plays a critical role in ciliary protein transport. However, the precise mechanisms of disease triggered by RPGR ORF15 mutations have yet to be clearly defined. There are two homologous genes in zebrafish, rpgra and rpgrb. Zebrafish rpgra has a single transcript homologous to human RPGR ORF15; rpgrb has two major transcripts: rpgrb ex1-17 and rpgrb ORF15, similar to human RPGR ex1-19 and RPGR ORF15, respectively. rpgrb knockdown in zebrafish resulted in both abnormal development and increased cell death in the dysplastic retina. However, the impact of knocking down rpgra in zebrafish remains undetermined. Here, we constructed a rpgra mutant zebrafish model to investigate the retina defect and related molecular mechanism. Methods: we utilized transcription activator-like effector nuclease (TALEN) to generate a rpgra mutant zebrafish. Western blot was used to determine protein expression. RT-PCR was used to quantify gene transcription levels. The visual function of embryonic zebrafish was detected by electroretinography. Immunohistochemistry was used to observe the pathological changes in the retina of mutant zebrafish and transmission electron microscope was employed to view subcellular structure of photoreceptor cells. Results: A homozygous rpgra mutant zebrafish with c.1675_1678delins21 mutation was successfully constructed. Despite the normal morphological development of the retina at 5 days post-fertilization, visual dysfunction was observed in the mutant zebrafish. Further histological and immunofluorescence assays indicated that rpgra mutant zebrafish retina photoreceptors progressively began to degenerate at 3-6 months. Additionally, the mislocalization of cone outer segment proteins (Opn1lw and Gnb3) and the accumulation of vacuole-like structures around the connecting cilium below the OSs were observed in mutant zebrafish. Furthermore, Rab8a, a key regulator of opsin-carrier vesicle trafficking, exhibited decreased expression and evident mislocalization in mutant zebrafish. Discussion: This study generated a novel rpgra mutant zebrafish model, which showed retinal degeneration. our data suggested Rpgra is necessary for the ciliary transport of cone-associated proteins, and further investigation is required to determine its function in rods. The rpgra mutant zebrafish constructed in this study may help us gain a better understanding of the molecular mechanism of retinal degeneration caused by RPGR ORF15 mutation and find some useful treatment in the future.

Project description:BACKGROUND:Retinal degenerative diseases affect millions of people and represent the leading cause of vision loss around the world. Retinal degeneration has been attributed to a wide variety of causes, such as disruption of genes involved in phototransduction, biosynthesis, folding of the rhodopsin molecule, and the structural support of the retina. The molecular pathogenesis of the biological events in retinal degeneration is unclear; however, the molecular basis of the retinal pathological defect can be potentially determined by gene-expression profiling of the whole retina. In the present study, we analyzed the differential gene expression profile of the retina from a wild-type zebrafish and phosphodiesterase 6c (pde6c) mutant. RESULTS:The datasets were downloaded from the Sequence Read Archive (SRA), and adaptors and unbiased bases were removed, and sequences were checked to ensure the quality. The reads were further aligned to the reference genome of zebrafish, and the gene expression was calculated. The differentially expressed genes (DEGs) were filtered based on the log fold change (logFC) (±4) and p-values (p?<?0.001). We performed gene annotation (molecular function [MF], biological process [BP], cellular component [CC]), and determined the functional pathways Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for the DEGs. Our result showed 216 upregulated and 3527 downregulated genes between normal and pde6c mutant zebrafish. These DEGs are involved in various KEGG pathways, such as the phototransduction (12 genes), mRNA surveillance (17 genes), phagosome (25 genes), glycolysis/gluconeogenesis (15 genes), adrenergic signaling in cardiomyocytes (29 genes), ribosome (20 genes), the citrate cycle (TCA cycle; 8 genes), insulin signaling (24 genes), oxidative phosphorylation (20 genes), and RNA transport (22 genes) pathways. Many more of all the pathway genes were down-regulated, while fewer were up-regulated in the retina of pde6c mutant zebrafish. CONCLUSIONS:Our data strongly indicate that, among these genes, the above-mentioned pathways' genes as well as calcium-binding, neural damage, peptidase, immunological, and apoptosis proteins are mostly involved in the retinal and neural degeneration that cause abnormalities in photoreceptors or retinal pigment epithelium (RPE) cells.

Dataset Information

A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration.

Publications

A Naturally-Derived Compound Schisandrin B Enhanced Light Sensation in the pde6c Zebrafish Model of Retinal Degeneration.

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