June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Unfolded Protein Response dysregulation prevents rhodopsin protein clearance and accelerates retinal degeneration in retinitis pigmentosa mouse model
Author Affiliations & Notes
  • Leon Chea
    Pathology, Stanford University School of Medicine, Stanford, California, United States
    Ophthalmology, Stanford University School of Medicine, Stanford, California, United States
  • Eun-Jin Lee
    Pathology, Stanford University School of Medicine, Stanford, California, United States
    Ophthalmology, Stanford University School of Medicine, Stanford, California, United States
  • Priscilla Chan
    University of Southern California, Los Angeles, California, United States
  • Jonathan H Lin
    Pathology, Stanford University School of Medicine, Stanford, California, United States
    Ophthalmology, Stanford University School of Medicine, Stanford, California, United States
  • Footnotes
    Commercial Relationships   Leon Chea, None; Eun-Jin Lee, None; Priscilla Chan, None; Jonathan Lin, None
  • Footnotes
    Support  The National Eye Institute of the National Institutes of Health (R01EY027335-JHL); VA Merit (I01-BX00284); and CIRM DISC2-10973.
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2214. doi:
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    • Get Citation

      Leon Chea, Eun-Jin Lee, Priscilla Chan, Jonathan H Lin; Unfolded Protein Response dysregulation prevents rhodopsin protein clearance and accelerates retinal degeneration in retinitis pigmentosa mouse model. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2214.

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

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Abstract

Purpose : Retinitis Pigmentosa (RP) causes retinal blindness due to loss of rods and later of cones . The P23H rhodopsin knock-in (P23H-KI) mouse develops retinal degeneration that closely mimics RP patients carrying the orthologous mutation. Previously, we found that P23H rhodopsin protein was robustly degraded in P23H-KI mouse retinas, and that Unfolded Protein Response (UPR) regulator genes promoted P23H rhodopsin protein degradation in heterologous cells in vitro. Here, we investigated the role of the UPR regulator gene, ATF6, in rhodopsin protein homeostasis in P23H-KI mice.

Methods : We compared retinas of ATF6-/-Rho+/P23H C57BL/B6 background mice with littermate control ATF6+/- Rho+/P23H mice from postnatal days 12-60. Whole retinas were collected for western blotting and qPCR analyses of Rhodopsin (1D4) and UPR gene/protein quantification. Enucleations were cryo-sectioned, H&E stained, and retinal laminar anatomy examined and quantified. Full-field scotopic and photopic electroretinography (ERG) recordings were measured on dark-adapted mice at p60.

Results : Significantly increased rhodopsin protein levels (1.91x; p=0.0406) were found in ATF6-/-Rho+/P23H retinas compared to ATF6+/- Rho+/P23H mice at p12. Interestingly, IRE1a and BiP/Grp78 protein levels; and Xbp1s and Hrd1 mRNA levels were also significantly increased in ATF6-/-Rho+/P23H retinas at early ages without gross changes in ONL thickness while Chop and Rhodopsin mRNA expression levels were not altered. By p60, ATF6-/-Rho+/P23H mice showed increased retinal degeneration in comparison to control mice in all retinal layers by histology and reduced rhodopsin protein levels by immunoblotting. However, full-field scotopic and photopic ERGs were within normal limits for both ATF6+/- Rho+/P23H and ATF6-/-Rho+/P23H mice at p60.

Conclusions : We conclude that ATF6 is required for efficient clearance of P23H rhodopsin protein in rod photoreceptors, and loss of ATF6 leads to hyperactivation of the IRE1-XBP1s signaling pathway of the UPR. Despite these compensatory changes, ATF6-/-Rho+/P23H mice develop more retinal degeneration as they age. Our findings show that UPR controls rhodopsin proteostasis in the retina and suggests that UPR activity influences the kinetics of retinal degeneration in RP patients expressing misfolded rhodopsin.

This is a 2021 ARVO Annual Meeting abstract.

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