June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Role of Receptor Interacting Protein Kinases in the Retinal Degeneration of S334ter and P23H Mutant Rat Models of Retinitis Pigmentosa
Author Affiliations & Notes
  • Zeinabsadat Mohammadi
    University of British Columbia, Vancouver, BC, Canada
  • Ishaq A Viringipurampeer
    University of British Columbia, Vancouver, BC, Canada
  • Kevin Gregory-Evans
    University of British Columbia, Vancouver, BC, Canada
  • Cheryl Y Gregory-Evans
    University of British Columbia, Vancouver, BC, Canada
  • Footnotes
    Commercial Relationships Zeinabsadat Mohammadi, None; Ishaq Viringipurampeer, None; Kevin Gregory-Evans, None; Cheryl Gregory-Evans, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 4629. doi:
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      Zeinabsadat Mohammadi, Ishaq A Viringipurampeer, Kevin Gregory-Evans, Cheryl Y Gregory-Evans; Role of Receptor Interacting Protein Kinases in the Retinal Degeneration of S334ter and P23H Mutant Rat Models of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4629.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Retinitis Pigmentosa (RP) is a clinically and genetically heterogeneous group of neurodegenerative diseases affecting photoreceptors and causing blindness. Understanding the cell death mechanisms in this group of genetic disorders is a key to the pathology of RP. Recent studies have suggested that RP is caused by retinal degeneration (RD) in rods as well as the subsequent death in nearby healthy cones. Despite this finding, the characteristics and pathway of cone cell death have remained unclear. Previous studies showed that the caspase-dependent pathway apoptosis is the main cell death pathway of RP, yet it seems caspase-independent pathways also are involved in the cell death process. This study investigates if the necroptosis cell death pathway was active in two transgenic models of RD, P23H and S334ter, where rhodopsin mutation causes defects in protein folding and sorting, respectively.

Methods: To investigate the cell death mechanism, the activity of necroptosis was tracked by expression of receptor interacting protein kinases, RIP1 and RIP3. Transgenic rats of seven different ages, from postnatal P10-P70, were investigated. Fresh retinas were removed from the eye cups to perform quantitative reverse transcription-polymerase chain reaction and western blotting. In other samples, the anterior segment was removed and eyes were processed for immunohistochemistry and TUNEL staining. Images were obtained by confocal scanning microscopy.

Results: The TUNEL assay demonstrated the highest number of dying cells in P23H and S334ter transgenic rats compared with age matched Sprague Dawley rats was at P17. RIP1 expression in the photoreceptor layer was highest at P17 and P28. Dual labelling showed a high level of RIP1 expression in cones at P28 in P23H retinas, whereas in the S334ter retina co-localization was seen at P17 and P28. Western blot of P23H retinal extracts demonstrated RIP3 expression at all tested time points, with the highest RIP3 expression at P17. In the S334ter retina RIP3 protein expression was highest at P28. RIP1 was not expressed in rods whereas RIP3 was present in both rods and cones.

Conclusions: This study showed that the RIP1- and RIP3-dependent cell death pathway was active in cones during RD in both rat models. This suggests that inhibiting this pathway may provide a new target for treatment of RP caused by rhodopsin mutations.

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