Now showing 1 - 3 of 3
  • Publication
    A brain-derived neurotrophic factor mimetic is sufficient to restore cone photoreceptor visual function in an inherited blindness model
    Controversially, histone deacetylase inhibitors (HDACi) are in clinical trial for the treatment of inherited retinal degeneration. Utilizing the zebrafish dyeucd6 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 inour dataset. Cotreatment 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.
      544Scopus© Citations 22
  • Publication
    Dawn and dusk peaks of outer segment phagocytosis, and visual cycle function require Rab28
    RAB28 is a farnesylated, ciliary G-protein. Patient variants in RAB28 are causative of autosomal recessive cone-rod dystrophy (CRD), an inherited human blindness. In rodent and zebrafish models, the absence of Rab28 results in diminished dawn, photoreceptor, outer segment phagocytosis (OSP). Here, we demonstrate that Rab28 is also required for dusk peaks of OSP, but not for basal OSP levels. This study further elucidated the molecular mechanisms by which Rab28 controls OSP and inherited blindness. Proteomic profiling identified factors whose expression in the eye or whose expression at dawn and dusk peaks of OSP is dysregulated by loss of Rab28. Notably, transgenic overexpression of Rab28, solely in zebrafish cones, rescues the OSP defect in rab28 KO fish, suggesting rab28 gene replacement in cone photoreceptors is sufficient to regulate Rab28-OSP. Rab28 loss also perturbs function of the visual cycle as retinoid levels of 11-cRAL, 11cRP, and atRP are significantly reduced in larval and adult rab28 KO retinae (p <.05). These data give further understanding on the molecular mechanisms of RAB28-associated CRD, highlighting roles of Rab28 in both peaks of OSP, in vitamin A metabolism and in retinoid recycling.
      43Scopus© Citations 2
  • Publication
    Peptigram: a web-based application for peptidomics data visualization
    Tandem mass spectrometry (MS/MS) techniques, developed for protein identification, are increasingly being applied in the field of peptidomics. Using this approach, the set of protein fragments observed in a sample of interest can be determined to gain insights into important biological processes such as signaling and other bioactivities. As the peptidomics era progresses, there is a need for robust and convenient methods to inspect and analyze MS/MS derived data. Here, we present Peptigram, a novel tool dedicated to the visualization and comparison of peptides detected by MS/MS. The principal advantage of Peptigram is that it provides visualizations at both the protein and peptide level, allowing users to simultaneously visualize the peptide distributions of one or more samples of interest, mapped to their parent proteins. In this way rapid comparisons between samples can be made in terms of their peptide coverage and abundance. Moreover, Peptigram integrates and displays key sequence features from external databases and links with peptide analysis tools to offer the user a comprehensive peptide discovery resource. Here, we illustrate the use of Peptigram on a data set of milk hydrolysates. For convenience, Peptigram is implemented as a web application, and is freely available for academic use at http://bioware.ucd.ie/peptigram.
      550Scopus© Citations 51