April 2010
Volume 51, Issue 13
ARVO Annual Meeting Abstract  |   April 2010
Activation of the Unfolded Protein Response in a Rat Model of ADRP
Author Affiliations & Notes
  • M. S. Gorbatyuk
    Molec Gen & Microbio,
    University of Florida, Gainesville, Florida
  • T. Knox
    Molec Gen & Microbio,
    University of Florida, Gainesville, Florida
  • M. M. LaVail
    Beckman Vision Center, UCSF School of Medicine, San Francisco, California
  • O. Gorbatyuk
    Molec Gen & Microbio,
    University of Florida, Gainesville, Florida
  • S. M. Noorwez
    University of Florida, Gainesville, Florida
  • W. W. Hauswirth
    Dept of Ophthalmology, Univ of Florida Coll of Medicine, Gainesville, Florida
  • J. H. Lin
    Pathology, Univ of CA San Diego Sch of Med, La Jolla, California
  • N. Muzyczka
    Molec Gen & Microbio,
    University of Florida, Gainesville, Florida
  • A. S. Lewin
    Molecular Genetics & Microbio,
    University of Florida, Gainesville, Florida
  • Footnotes
    Commercial Relationships  M.S. Gorbatyuk, None; T. Knox, None; M.M. LaVail, None; O. Gorbatyuk, None; S.M. Noorwez, None; W.W. Hauswirth, AGCT, P; J.H. Lin, None; N. Muzyczka, None; A.S. Lewin, None.
  • Footnotes
    Support  Foundation Fighting Blindness TA-GT4090-0479-UFL, TA-GT-0507-0384, NIH grants EY13729, EY11123, EY08571, NIH Grants EY01919, EY06842, EY02162 and EY013280; That Man May See, Inc. (MML); and Research
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 5810. doi:
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    • Get Citation

      M. S. Gorbatyuk, T. Knox, M. M. LaVail, O. Gorbatyuk, S. M. Noorwez, W. W. Hauswirth, J. H. Lin, N. Muzyczka, A. S. Lewin; Activation of the Unfolded Protein Response in a Rat Model of ADRP. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5810.

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

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Purpose: : Autosomal dominant retinitis pigmentosa (ADRP) is frequently associated with mutation of the gene (Rho) for rod cell opsin. The mechanism of retinal degeneration in P23H rhodopsin photoreceptors is tightly associated with misfolded opsin, which can cause endoplasmic reticulum overload (ER stress), activates the unfolded protein response (UPR) and triggers apoptosis. The goal of this project is to study the ER stress signaling network in transgenic animals to further validate new therapeutic targets for ADRP gene therapy.

Methods: : We isolated retinas from postnatal day (P) 30 P23H (line 3) Rho transgenic rats and Sprague-Dawley (SD) wild-type rats to study the activation of ER stress signaling by monitoring the peIF2α, sXbp1, CHOP, pATF6, caspase-7 by immunoblots or by RT-PCR.

Results: : We found that in P23H Rho rats, photoreceptors levels of cleaved ATF6, pEIF2α, CHOP and caspase-7 were much higher compared to SD rats. For example, in P23H-3 Rhorats, we observed up to a 3-fold increase in the cleaved pATF6 50kD protein, a 51% increase in peIF2α, a 26% increase in the level of CHOP proteinand an almost 4-fold increase in activated caspase-7. At P30 we also observed persistence of the IRE1 pathway in transgenic retinas. The level of spliced Xbp1 mRNA was 4-fold higher in P23HRhoratscompared to wild-type rats.

Conclusions: : Our findings indicate that the misfolded opsin activates the UPR signaling in P23H Rho rats and this could be a trigger of apoptosis in ADRP photoreceptors. We also propose that pro-apoptotic CHOP protein and caspase-7 could be potential candidates for the future ADRP gene therapy.

Keywords: retina • apoptosis/cell death • retinal degenerations: cell biology 

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