PUBLICATION

A Brain-Derived Neurotrophic Factor Mimetic Is Sufficient to Restore Cone Photoreceptor Visual Function in an Inherited Blindness Model

Authors
Daly, C., Shine, L., Heffernan, T., Deeti, S., Reynolds, A.L., O'Connor, J.J., Dillon, E.T., Duffy, D.J., Kolch, W., Cagney, G., Kennedy, B.N.
ID
ZDB-PUB-170914-3
Date
2017
Source
Scientific Reports   7: 11320 (Journal)
Registered Authors
Kennedy, Breandan N., Reynolds, Alison
Keywords
Hereditary eye disease, Mechanisms of disease, Neurodegeneration
MeSH Terms
  • Vision, Ocular*/drug effects
  • Vision, Ocular*/genetics
  • Male
  • Retina/drug effects
  • Retina/metabolism
  • Retina/pathology
  • Signal Transduction
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
  • Proteome
  • Proteomics/methods
  • Molecular Mimicry*
  • Brain-Derived Neurotrophic Factor/metabolism*
  • Brain-Derived Neurotrophic Factor/pharmacology
  • Mutation
  • Blindness/diagnosis
  • Blindness/drug therapy
  • Blindness/genetics
  • Blindness/physiopathology*
  • Retinal Cone Photoreceptor Cells/drug effects
  • Retinal Cone Photoreceptor Cells/metabolism*
  • Histone Deacetylase Inhibitors/pharmacology
  • Zebrafish
  • Animals
  • Disease Models, Animal
  • Receptor, trkB/metabolism
  • Electroretinography
  • Genetic Diseases, Inborn/diagnosis
  • Genetic Diseases, Inborn/drug therapy
  • Genetic Diseases, Inborn/genetics
  • Genetic Diseases, Inborn/physiopathology*
(all 32)
PubMed
28900183 Full text @ Sci. Rep.
Abstract
Controversially, histone deacetylase inhibitors (HDACi) are in clinical trial for the treatment of inherited retinal degeneration. Utilizing the zebrafish dye ucd6 model, we determined if treatment with HDACi can rescue cone photoreceptor-mediated visual function. dye exhibit defective visual behaviour and retinal morphology including ciliary marginal zone (CMZ) cell death and decreased photoreceptor outer segment (OS) length, as well as gross morphological defects including hypopigmentation and pericardial oedema. HDACi treatment of dye results in significantly improved optokinetic (OKR) (~43 fold, p < 0.001) and visualmotor (VMR) (~3 fold, p < 0.05) responses. HDACi treatment rescued gross morphological defects and reduced CMZ cell death by 80%. Proteomic analysis of dye eye extracts suggested BDNF-TrkB and Akt signaling as mediators of HDACi rescue in our dataset. Co-treatment with the TrkB antagonist ANA-12 blocked HDACi rescue of visual function and associated Akt phosphorylation. Notably, sole treatment with a BDNF mimetic, 7,8-dihydroxyflavone hydrate, significantly rescued dye visual function (~58 fold increase in OKR, p < 0.001, ~3 fold increase in VMR, p < 0.05). In summary, HDACi and a BDNF mimetic are sufficient to rescue retinal cell death and visual function in a vertebrate model of inherited blindness.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
WTchemical treatment by environment: trichostatin A, chemical treatment by environment: ANA-12Day 5
atp6v0e1ucd6/ucd6standard conditionsDay 5
atp6v0e1ucd6/ucd6standard conditionsDay 5
atp6v0e1ucd6/ucd6standard conditionsDay 5
atp6v0e1ucd6/ucd6standard conditionsDay 5
atp6v0e1ucd6/ucd6standard conditionsDay 5
atp6v0e1ucd6/ucd6standard conditionsDay 5
atp6v0e1ucd6/ucd6standard conditionsDay 5
atp6v0e1ucd6/ucd6standard conditionsDay 5
atp6v0e1ucd6/ucd6standard conditionsDay 5
1 - 10 of 38
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ucd6
    		Small Deletion
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    blindnessatp6v0e1ucd6/ucd6standard conditionsTAS
    1 - 1 of 1
    Show
    Sequence Targeting Reagents
    No data available
    Fish
    Fish
    atp6v0e1ucd6/ucd6
    WT
    1 - 2 of 2
    Show
    Antibodies
    Name Type Antigen Genes Isotypes Host Organism
    Ab1-actbmonoclonal
      		IgG1Mouse
      Ab1-bdnfpolyclonalRabbit
      Ab1-ntrk2polyclonalRabbit
      Ab3-aktpolyclonal
        		Rabbit
        Ab8-aktpolyclonal
          		Rabbit
          Ab45-h3polyclonal
            		IgGRabbit
            1 - 6 of 6
            Show
            Orthology
            No data available
            Engineered Foreign Genes
            No data available
            Mapping
            No data available
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            Citation
            Daly, C., Shine, L., Heffernan, T., Deeti, S., Reynolds, A.L., O'Connor, J.J., Dillon, E.T., Duffy, D.J., Kolch, W., Cagney, G., Kennedy, B.N. (2017) A Brain-Derived Neurotrophic Factor Mimetic Is Sufficient to Restore Cone Photoreceptor Visual Function in an Inherited Blindness Model. Scientific Reports. 7:11320.