Retinitis pigmentosa (RP) mouse cone transcriptom change with Txnip treatment
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ABSTRACT:
PROVIDER: PRJNA678960 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13073660_1.fastq.gz | Fastqsanger.gz | |||
| SRR13073660_2.fastq.gz | Fastqsanger.gz | |||
| SRR13073661_1.fastq.gz | Fastqsanger.gz | |||
| SRR13073661_2.fastq.gz | Fastqsanger.gz | |||
| SRR13073662_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: To identifiy mRNA changes in retinitis pigmentosa (RP) cone photoreceptors with Txnip overexpression treatment, which improved RP cone survival and visual acuity. Methods: two RP mouse strains, rd1 and Rho-/-, were injected with AAV-Txnip or AAV-H2BGFP control subretinally at P0. Retinas were dissected out at P21 for rd1 and P90 for Rho-/-. 1,000 H2BGFP labeled cones per retina sample were FACS sorted out, and subject for RNA-sequencing. Results: >1,400 genes in P21 rd1 and >700 genes in Rho-/- were found differentially expressed with Txnip treatment. Conclusions: 25 genes are in common between P21 rd1 and P90 Rho-/- with Txnip treatment. On this list, notably, three mitochondrial Electron Transport Chain (ETC) genes were up-regulated.
2021-01-20 | GSE161622 | GEO
Project description:Purpose: To identifiy mRNA changes in wt cone photoreceptors with Txnip overexpression treatment, which improved retinitis pigmentosa (RP) cone survival and visual acuity. Methods: two wt mouse strains, BALB/c and C57BL/6J were injected with AAV-Txnip or AAV-H2BGFP control subretinally at P0. Retinas were dissected out at P21 for BALB/c and P35 for C57BL/6J. 1,000 H2BGFP labeled cones per retina sample were FACS sorted out, and subject for RNA-sequencing. Results: only ~70 genes in P21 BALB/c and 1 genes in C57BL/6J were found differentially expressed with Txnip treatment. Only 1 genes (i.e. Txnip) were in commonly upregulated between the two lists. Conclusions: Txnip seems to be not changing RNA expression much in wt cones. Instead, its major function to rescue RP cones may lay in protein-protein interactions.
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Project description:Recessive retinitis pigmentosa (RP) is often caused by nonsense mutations that lead to low mRNA levels as a result of nonsense-mediated decay. Some RP genes are expressed at detectable levels in leukocytes as well as in the retina. We designed a microarray-based method to find recessive RP genes based on low lymphoblast mRNA expression levels Keywords: Recessive mutations; mRNA expression; nonsense mediated-decay; retinitis pigmentosa; lymphocyte; Affymetrix genechip Human Genome U133Plus2.0.
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Project description:Cone photoreceptor cell death in inherited retinal diseases, such as Retinitis Pigmentosa (RP), leads to the loss of accurate and color vision and ultimately blindness. In RP, a vast number of mutations are affecting the structure and function of rod photoreceptors while cones remain mutation-free. Once majority of rods have degenerated cones are dying secondarily due to the increased oxidative stress, inflammation and loss of structural and nutritional support normally provided by rods. Here we demonstrated that secondary cone cell death in animal models for RP is governed by an increased activity of histone deacetylates (HDACs). A single intravitreal injection of an HDAC inhibitor at a late stage of the disease, when majority of rods have already degenerated, is sufficient to delay cone death and support long-term cone survival. Surviving cones are retaining functionality and are mediating light-driven ganglion cell responses. RNA-seq analysis of surviving cones demonstrated that HDAC inhibition affords multi-level protection trough regulation of different prosurvival pathways including MAPK, PI3K-AKT and autophagy. These study suggest a unique possibility for targeted pharmacological protection of both primary degenerating rods and mutation-free secondary dying cones and creates hope to maintain vision in RP patients independent of the disease stage.
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Project description:Retinal dehydrogenase 12 (RDH12) is a photoreceptor NADPH-dependent retinal reductase enzyme, which converts all-trans-retinal to all-trans-retinol. In rare cases, heterozygous variants in RDH12 are associated with a mild, late-onset autosomal dominant (AD) retinitis pigmentosa (RP). There are no dominant RDH12 animal models, hence, we generated retinal organoids from human induced pluripotent stem cells (hiPSC) derived from dermal fibroblasts from a RDH12-AD patient with the heterozygous pathogenic variant c.759del p.(Phe254Leufs*24) and an unrelated unaffected individual (WT). Retinal organoids were characterised at different stages of differentiation; at 18-weeks there were no differences in rod and cone photoreceptors with correct localisation of RDH12 in the photoreceptor inner segments in both WT and RDH12-AD. Transmission electron microscopy on week 37 retinal organoids showed a normal outer limiting membrane and mitochondria, but photoreceptors were 1.8 times less abundant and shorter in RDH12-AD mutant compared to WT. Transcriptomic analyses on week 44 retinal organoids revealed visual cone function, retinol biosynthesis and the vitamin A pathway are highly affected in RDH12-AD retinal organoids. Our study is the first to describe a human RDH12 retinal organoid model, and we found subtle differences between the WT and mutant at later stages of photoreceptor differentiation. This is in keeping with the milder disease course seen in humans, but it provides insights into the aetiology and possible targets for future therapeutic development.
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