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Cell Rep. 2016 Sep 27;17(1):69-85. doi: 10.1016/j.celrep.2016.08.073.

NAMPT-Mediated NAD(+) Biosynthesis Is Essential for Vision In Mice.

Author information

1
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Neuroscience Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Neuroscience Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
4
Department of Ophthalmology, Keio University School of Medicine, Tokyo 160-8582, Japan.
5
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
6
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: imaishin@wustl.edu.
7
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: apte@vision.wustl.edu.

Abstract

Photoreceptor death is the endpoint of many blinding diseases. Identifying unifying pathogenic mechanisms in these diseases may offer global approaches for facilitating photoreceptor survival. We found that rod or cone photoreceptor-specific deletion of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the major NAD(+) biosynthetic pathway beginning with nicotinamide, caused retinal degeneration. In both cases, we could rescue vision with nicotinamide mononucleotide (NMN). Significantly, retinal NAD(+) deficiency was an early feature of multiple mouse models of retinal dysfunction, including light-induced degeneration, streptozotocin-induced diabetic retinopathy, and age-associated dysfunction. Mechanistically, NAD(+) deficiency caused metabolic dysfunction and consequent photoreceptor death. We further demonstrate that the NAD(+)-dependent mitochondrial deacylases SIRT3 and SIRT5 play important roles in retinal homeostasis and that NAD(+) deficiency causes SIRT3 dysfunction. These findings demonstrate that NAD(+) biosynthesis is essential for vision, provide a foundation for future work to further clarify the mechanisms involved, and identify a unifying therapeutic target for diverse blinding diseases.

KEYWORDS:

NAD(+); metabolism; mitochondria; neurodegeneration; photoreceptor; retina; sirtuins

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PMID:
27681422
PMCID:
PMC5104206
DOI:
10.1016/j.celrep.2016.08.073
[Indexed for MEDLINE]
Free PMC Article

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