July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Photoreceptor metabolic reprogramming provides survival advantage in acute stress while causing chronic degeneration
Author Affiliations & Notes
  • Thomas Wubben
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Mercy Pawar
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Andrew Smith
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Kevin Toolan
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Heather Hager
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Cagri G Besirli
    Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Footnotes
    Commercial Relationships   Thomas Wubben, University of Michigan (P); Mercy Pawar, None; Andrew Smith, None; Kevin Toolan, None; Heather Hager, None; Cagri Besirli, University of Michigan (P)
  • Footnotes
    Support  VitreoRetinal Surgery Foundation Research Award
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4448. doi:
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    • Get Citation

      Thomas Wubben, Mercy Pawar, Andrew Smith, Kevin Toolan, Heather Hager, Cagri G Besirli; Photoreceptor metabolic reprogramming provides survival advantage in acute stress while causing chronic degeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4448.

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

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Abstract

Purpose : Photoreceptor death is the root cause of vision loss in many retinal disorders. There is an unmet need for neuroprotective modalities to improve photoreceptor survival. Recent studies demostrated that reprogramming metabolism and enhancing glycolysis may be a novel neuroprotective strategy. As such, we genetically reprogrammed photoreceptor metabolism by altering PKM2 expression in photoreceptors and characterized the effect of Pkm2 deletion on functioning and survival of photoreceptors at baseline and during acute outer retinal stress.

Methods : Pkm2 was selectively deleted from rod photoreceptors by crossing mice with Lox-P sites flanking Pkm2-specific exon 10 (Pkm2flox/flox) with Rho-Cre mice. Immunohistochemistry (IHC) and western blot analysis were utilized to address the abundance and location of PKM2 and its isoenzyme, PKM1. RT-PCR analyzed changes in the expression of genes involved in glucose metabolism. The effect of PKM2 deletion on the functioning and survival of the photoreceptors was examined using optokinetic tracking, OCT, ERG, and histology. Outer retinal stress was induced via experimental retinal detachment, TUNEL staining and caspase activity were assessed after 3 days, and photoreceptor survival was assessed after 2 months via histology.

Results : IHC and western blot analysis validated the rod-specific knockdown of PKM2 protein levels when Pkm2 was deleted (Pkm2-/-) and showed an increase in PKM1 in the outer retina. Additionally, Pkm2 deletion led to an increase in the expression of genes involved in glucose metabolism. These molecular changes resulted in a small decrease in outer retinal thickness and outer nuclear layer cell counts in the Pkm2-/- mice on OCT and histologic analysis. Accordingly, the Pkm2-/- mice showed a small decrease in the scotopic a-wave amplitude as evaluated by ERG. In contrast, during experimental retinal detachment, Pkm2 deletion resulted in reduced entrance into the apoptosis cascade as seen by decreased photoreceptor TUNEL staining and caspase activity while showing improved photoreceptor survival 2 months after retinal detachment.

Conclusions : This study shows that PKM2 to PKM1 metabolic reprogramming decreases photoreceptor death during outer retinal stress and provides evidence that reprogramming of photoreceptor metabolism is a novel photoreceptor neuroprotective strategy that may be utilized in many retinal disorders.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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