June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Pathologic poly(ADP-ribose) polymerase (PARP) activation contributes to retinal degeneration in mice with retinal NAD+ deficiency
Author Affiliations & Notes
  • Jonathan Lin
    Ophthalmology & Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Andrea Santeford
    Ophthalmology & Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Teresa Chen
    Ophthalmology & Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Mitsukuni Yoshida
    Developmental Biology, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Shin-ichiro Imai
    Developmental Biology, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Rajendra S Apte
    Ophthalmology & Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States
    Developmental Biology, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Footnotes
    Commercial Relationships   Jonathan Lin, None; Andrea Santeford, None; Teresa Chen, None; Mitsukuni Yoshida, None; Shin-ichiro Imai, None; Rajendra Apte, None
  • Footnotes
    Support  NIH Grants R01EY019287, P30EY02687, T32GM007200, UL1TR000448, TL1TR000449; Carl Marshall Reeves and Mildred Almen Reeves Foundation; Research to Prevent Blindness; Schulak Family Gift Fund for Retinal Research; Jeffrey Fort Innovation Fund; Hope For Vision
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4533. doi:
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      Jonathan Lin, Andrea Santeford, Teresa Chen, Mitsukuni Yoshida, Shin-ichiro Imai, Rajendra S Apte; Pathologic poly(ADP-ribose) polymerase (PARP) activation contributes to retinal degeneration in mice with retinal NAD+ deficiency. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4533.

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

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Abstract

Purpose : We previously demonstrated that the dominant mammalian NAD+ biosynthetic pathway mediated by nicotinamide phosphoribosyltransferase (NAMPT) is essential for photoreceptor survival and vision in mice. However, why photoreceptors are exquisitely sensitive to perturbations in the NAMPT-mediated pathway remains unclear. This study tests the hypothesis that NAD+ utilization due to pathologic poly(ADP-ribose) polymerase (PARP) activation contributes to retinal degeneration in mice with retinal NAD+ deficiency.

Methods : We generated mice with Nampt deleted specifically from rod photoreceptors (Nampt-rod/-rod) using the Cre-lox system and quantified retinal PARP activation by Western blotting. Next, we measured the reductive capacity and cell survival of 661W photoreceptor cells treated with various combinations of the NAMPT inhibitor FK866 (20 μM) and the PARP inhibitors ABT-888 (2 nM) and BYK204165 (400 nM) with the WST-1 and calcein AM assays, respectively. Finally, we gave Nampt-rod/-rod mice daily intraperitoneal injections of ABT-888 (20 mg/kg body weight) beginning at postnatal day 5 (P5) and tested retinal function at P28-P30 with electroretinography (ERG). For all analysis, we considered p < .05 to be statistically significant.

Results : We found that retinas from 3-week-old Nampt-rod/-rod mice contained more PARylated proteins at 3 weeks compared to NamptF/F littermates, indicating substantial PARP activation. In addition, treatment with either PARP inhibitor ABT-888 or BYK204165 significantly reduced the toxic effect of FK866-mediated NAMPT inhibition on the reductive capacity (p < .01) and cell survival (p < .05) of photoreceptor cells. Finally, Nampt-rod/-rod mice treated daily with the PARP inhibitor ABT-888 beginning at P5 had improved scotopic (p < .05) and photopic (p < .01) ERG responses compared to vehicle-treated Nampt-rod/-rod mice at P28-P30.

Conclusions : Our results show that pathologic PARP activation contributes to retinal degeneration in mice with retinal NAD+ deficiency. Our findings suggest that PARP inhibition may have therapeutic efficacy against diverse blinding diseases. Future studies will test whether PARP activation is pathologic in other mouse models of retinal degeneration and explore the therapeutic efficacy of using PARP inhibitors in conjunction with NAD+ intermediates.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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