September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
The nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthetic pathway is essential for photoreceptor survival and vision
Author Affiliations & Notes
  • Jonathan B Lin
    Ophthalmology & Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Shunsuke Kubota
    Ophthalmology & Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Norimitsu Ban
    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
  • Andrea Santeford
    Ophthalmology & Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Abdoulaye Sene
    Ophthalmology & Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Miyuki Kubota
    Ophthalmology & Visual Sciences, Washington University School of Medicine, Saint Louis, Missouri, United States
  • Kazuo Tsubota
    Ophthalmology, Keio University School of Medicine, Tokyo, Japan
  • Jun Yoshino
    Medicine, 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; Shunsuke Kubota, None; Norimitsu Ban, None; Mitsukuni Yoshida, None; Andrea Santeford, None; Abdoulaye Sene, None; Miyuki Kubota, None; Kazuo Tsubota, Metro Biotech (C); Jun Yoshino, None; Shin-ichiro Imai, Washington University IP licensed to Metro Midwest Biotech (P); Rajendra Apte, Washington University IP licensed to Metro Midwest Biotech (P)
  • Footnotes
    Support  NIH Grants R01EY019287 (RSA), AG024150 (SI), AG037457 (SI), KL2TR000450 (JY), P30DK56341 (JY), P30DK02057 (JY), P30EY02687 (Core Grant), T32GM07200 (JBL), UL1TR000448 (JBL), TL1TR000449 (JBL); the Robert Machemer Foundation (SK); the Reeves Foundation (RSA); Research to Prevent Blindness (RSA); the Lacy Foundation (SK, AS); the American Federation for Aging Research (RSA, JBL); the Hope Center (RSA, SI), and the Central Society for Clinical and Translational Research (JY).
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2264. doi:
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      Jonathan B Lin, Shunsuke Kubota, Norimitsu Ban, Mitsukuni Yoshida, Andrea Santeford, Abdoulaye Sene, Miyuki Kubota, Kazuo Tsubota, Jun Yoshino, Shin-ichiro Imai, Rajendra S Apte; The nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD+ biosynthetic pathway is essential for photoreceptor survival and vision. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2264.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : Photoreceptor death is the common final pathway of many blinding diseases, including age-related macular degeneration, diabetic retinopathy, and inherited retinal degenerations. While the coenzyme nicotinamide adenine dinucleotide (NAD+) has been shown to be important in neurodegeneration, its role in photoreceptor death is relatively unexplored. Therefore, we investigated the role of the dominant mammalian NAD+ biosynthetic pathway, i.e. the nicotinamide phosphoribosyltransferase (NAMPT)-mediated pathway, in photoreceptor survival.

Methods : We generated mice lacking Nampt specifically from rod (Nampt-r/-r) and cone photoreceptors (Nampt-c/-c) and assessed photoreceptor survival/function in these mice with fundus biomicroscopy, histopathology, electroretinography (ERG), and optokinetic reflex testing. In parallel, we treated the cone photoreceptor-like 661W cell line with the NAMPT inhibitor FK866 to further characterize how NAD+ depletion affects photoreceptor metabolism and ultimately leads to their demise. [JBL/SK = equal contributors]

Results : Nampt-r/-r mice exhibited diffuse atrophy of the neurosensory retina on fundus biomicroscopy and complete absence of the outer nuclear layer on histopathology by 6 weeks. This retinal degeneration led to dramatic retinal dysfunction on ERG (scotopic a-waves: F1,13=90.1, p<.0001; scotopic b-waves: F1,13=247.8, p<.0001; photopic b-waves: F1,13=281.4, p< .0001). Analogously, Nampt-c/-c mice displayed predominately cone-specific degeneration on fundus biomicroscopy and ERG (scotopic a-waves: F1,16=2.6, p=.1255; scotopic b-waves: F1,16=64.6, p<.0001; photopic b-waves: F1,16=230.2, p<.0001), suggesting a cell-specific effect of Nampt deletion. Exogenous supplementation with nicotinamide mononucleotide (NMN) to bypass the NAMPT-catalyzed reaction rescued retinal function on ERG in both Nampt-r/-r and Nampt-c/-c mice (p<.05). Inhibiting the NAMPT-mediated pathway in photoreceptors led to rapid NAD+ depletion and, subsequently, to mitochondrial dysfunction and metabolic catastrophe.

Conclusions : Our results support a crucial role for the NAMPT-mediated NAD+ biosynthetic pathway to regenerate NAD+ from nicotinamide to maintain the NAD+ levels necessary to sustain photoreceptor metabolism. These findings identify a potential unifying therapeutic target for diverse blinding diseases of different etiologies.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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