Dataset Information

Selective Histone Deacetylase 6 Inhibitors Restore Cone Photoreceptor Vision or Outer Segment Morphology in Zebrafish and Mouse Models of Retinal Blindness.

ABSTRACT: Blindness arising from retinal or macular degeneration results in significant social, health and economic burden. While approved treatments exist for neovascular ('wet') age-related macular degeneration, new therapeutic targets/interventions are needed for the more prevalent atrophic ('dry') form of age-related macular degeneration. Similarly, in inherited retinal diseases, most patients have no access to an effective treatment. Although macular and retinal degenerations are genetically and clinically distinct, common pathological hallmarks can include photoreceptor degeneration, retinal pigment epithelium atrophy, oxidative stress, hypoxia and defective autophagy. Here, we evaluated the potential of selective histone deacetylase 6 inhibitors to preserve retinal morphology or restore vision in zebrafish atp6v0e1 -/- and mouse rd10 models. Histone deacetylase 6 inhibitor, tubastatin A-treated atp6v0e1 -/- zebrafish show marked improvement in photoreceptor outer segment area (44.7%, p = 0.027) and significant improvement in vision (8-fold, p ? 0.0001). Tubastatin A-treated rd10/rd10 retinal explants show a significantly (p = 0.016) increased number of outer-segment labeled cone photoreceptors. In vitro, ATP6V0E1 regulated HIF-1? activity, but significant regulation of HIF-1? by histone deacetylase 6 inhibition in the retina was not detected. Proteomic profiling identified ubiquitin-proteasome, phototransduction, metabolism and phagosome as pathways, whose altered expression correlated with histone deacetylase 6 inhibitor mediated restoration of vision.

SUBMITTER: Sundaramurthi H

PROVIDER: S-EPMC7479070 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Selective Histone Deacetylase 6 Inhibitors Restore Cone Photoreceptor Vision or Outer Segment Morphology in Zebrafish and Mouse Models of Retinal Blindness.

Sundaramurthi Husvinee H Roche Sarah L SL Grice Guinevere L GL Moran Ailis A Dillion Eugene T ET Campiani Giuseppe G Nathan James A JA Kennedy Breandán N BN

Frontiers in cell and developmental biology 20200826

Blindness arising from retinal or macular degeneration results in significant social, health and economic burden. While approved treatments exist for neovascular ('<i>wet'</i>) age-related macular degeneration, new therapeutic targets/interventions are needed for the more prevalent atrophic ('<i>dry'</i>) form of age-related macular degeneration. Similarly, in inherited retinal diseases, most patients have no access to an effective treatment. Although macular and retinal degenerations are geneti ...[more]

PMID: 32984302

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Project description:PurposeMutations in the gene ARL13B cause the classical form of Joubert syndrome, an autosomal recessive ciliopathy with variable degrees of retinal degeneration. As second-site modifier alleles can contribute to retinal pathology in ciliopathies, animal models provide a unique platform to test how genetic interactions modulate specific phenotypes. In this study, we analyzed the zebrafish arl13b mutant for retinal degeneration and for epistatic relationships with the planar cell polarity protein (PCP) component vangl2.MethodsPhotoreceptor and cilia structure was examined by light and electron microscopy. Immunohistochemistry was performed to examine ciliary markers. Genetic interactions were tested by pairwise crosses of heterozygous animals. Genetic mosaic animals were generated by blastula transplantation and analyzed by fluorescence microscopy.ResultsAt 5 days after fertilization, photoreceptor outer segments were shorter in zebrafish arl13b-/- mutants compared to wild-type larvae, no overt signs of retinal degeneration were observed by light or electron microscopy. Starting at 14 days after fertilization (dpf) and continuing through 30 dpf, cells lacking Arl13b died following transplantation into wild-type host animals. Photoreceptors of arl13b-/-;vangl2-/- mutants were more compromised than the photoreceptors of single mutants. Finally, when grown within a wild-type retina, the vangl2-/- mutant cone photoreceptors displayed normal basal body positioning.ConclusionsWe show that arl13b-/- mutants have shortened cilia and photoreceptor outer segments and exhibit a slow, progressive photoreceptor degeneration that occurs over weeks. The data suggest that loss of Arl13b leads to slow photoreceptor degeneration, but can be exacerbated by the loss of vangl2. Importantly, the data show that Arl13b can genetically and physically interact with Vangl2 and this association is important for normal photoreceptor structure. The loss of vangl2, however, does not affect basal body positioning.

Dataset Information

Selective Histone Deacetylase 6 Inhibitors Restore Cone Photoreceptor Vision or Outer Segment Morphology in Zebrafish and Mouse Models of Retinal Blindness.

Publications

Selective Histone Deacetylase 6 Inhibitors Restore Cone Photoreceptor Vision or Outer Segment Morphology in Zebrafish and Mouse Models of Retinal Blindness.

Similar Datasets

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