June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Regulation of proteasomal biogenesis in photoreceptors
Author Affiliations & Notes
  • Yixiao Wang
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Eric Nayman
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Katya Lobanova
    Ophthalmology, University of Florida, Gainesville, Florida, United States
  • Footnotes
    Commercial Relationships   Yixiao Wang, None; Eric Nayman, None; Katya Lobanova, None
  • Footnotes
    Support  EY030043
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 1278. doi:
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      Yixiao Wang, Eric Nayman, Katya Lobanova; Regulation of proteasomal biogenesis in photoreceptors. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1278.

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

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Abstract

Purpose : Proteasomal overload is a common stress factor observed in several mouse models of retinal degeneration in which photoreceptors experience problems with protein folding. Several studies have demonstrated that stimulation of proteasomal activity improves photoreceptor survival in preclinical models of retinal disease. Approaches to increase the total cellular pool of proteasomes might have even stronger therapeutic potential. In this study, we used a Cre-lox system to investigate mechanistic Target Of Rapamycin Complex 1 (mTORC1) activation as a novel approach to stimulate proteasomal biogenesis and explored its therapeutic potential in a mouse model of proteasomal overload.

Methods : To understand the role of mTORC1 in proteasomal biogenesis, we analyzed the retinal phenotype of Tsc2fl/fl/iCre75+ mice. Proteasomal expression and activation of the mTORC1 pathway were analyzed by western blotting and qRT-PCR. Retinal health was evaluated with Optical Coherence Tomography, Funduscopy, and Hematoxylin & Eosin staining of retinal sections. Retinal function was assessed with Electroretinography. Animals of both sexes were used, and all mice tested negative for Rd1 and Rd8 mutations. All mice were followed up to 6 months of age.

Results : Genetic activation of mTORC1 in rods stimulated the biogenesis of major components of the proteasome, the 19S regulator and 20S core particle, on both transcriptional and translational levels. Quantitative western blotting of representative proteasomal subunits (PSMD1, PSMD11, PSMA1-A7) indicated there was an ~ 50% (n=3, p≤0.05) increase in the total levels of proteasomes in rods. Morphometric analysis did not reveal any photoreceptor loss in these mice. Finally, we found that genetic stimulation of mTORC1 in P23H mice bearing Proline-to-Histidine substitution at 23rd codon in the rhodopsin gene slowed the photoreceptor loss by approximately 3 months (n=10, p≤0.05).

Conclusions : Our data suggest that activation of mTORC1 in rods is an effective approach to stimulate proteasomal biogenesis. We also found that stimulation of mTORC1 delays photoreceptor loss in a mouse model of proteasomal overload. Future studies will determine the contributions of the individual pathways controlled by mTORC1 (proteasomal biogenesis, autophagy, translation, glucose metabolism) to the observed therapeutic effects.

This is a 2020 ARVO Annual Meeting abstract.

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