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
-
- Animals
- Blindness/diagnosis
- Blindness/drug therapy
- Blindness/genetics
- Blindness/physiopathology*
- Brain-Derived Neurotrophic Factor/metabolism*
- Brain-Derived Neurotrophic Factor/pharmacology
- Disease Models, Animal
- Electroretinography
- Genetic Diseases, Inborn/diagnosis
- Genetic Diseases, Inborn/drug therapy
- Genetic Diseases, Inborn/genetics
- Genetic Diseases, Inborn/physiopathology*
- Histone Deacetylase Inhibitors/pharmacology
- Male
- Molecular Mimicry*
- Mutation
- Proteome
- Proteomics/methods
- Receptor, trkB/metabolism
- Retina/drug effects
- Retina/metabolism
- Retina/pathology
- Retinal Cone Photoreceptor Cells/drug effects
- Retinal Cone Photoreceptor Cells/metabolism*
- Signal Transduction
- Vision, Ocular*/drug effects
- Vision, Ocular*/genetics
- Zebrafish
- Zebrafish Proteins/chemistry
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 28900183 Full text @ Sci. Rep.
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.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping