@article{a4006c8277364afea527d054b901430a,
title = "NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice",
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",
author = "Lin, {Jonathan B.} and Shunsuke Kubota and Norimitsu Ban and Mitsukuni Yoshida and Andrea Santeford and Abdoulaye Sene and Rei Nakamura and Nicole Zapata and Miyuki Kubota and Kazuo Tsubota and Jun Yoshino and Imai, {Shin ichiro} and Apte, {Rajendra S.}",
note = "Funding Information: This work was supported by NIH grants R01EY019287 (R.S.A.), AG024150 (S.I.), AG037457 (S.I.), KL2TR000450 (J.Y.), P30DK56341 (J.Y.), P30DK020579 (J.Y.), DK104995 (J.Y.), and P30EY02687 (Vision Core Grant); the Carl Marshall Reeves and Mildred Almen Reeves Foundation (R.S.A.); a Physician-Scientist Award from Research to Prevent Blindness (R.S.A.); the Hope Center (R.S.A. and S.I.), the Lacy Foundation (A. Sene and S.K.); the American Federation for Aging Research (R.S.A.); the Schulak Family Gift Fund for Retinal Research (R.S.A.); the Jeffrey Fort Innovation Fund (R.S.A.); Hope For Vision (R.S.A.); the Robert Machemer Foundation (S.K.); and the Central Society for Clinical and Translational Research (J.Y.). Additional funding comes from an unrestricted grant to the Department of Ophthalmology and Visual Sciences of Washington University School of Medicine from Research to Prevent Blindness. J.B.L. was supported by the Washington University in St. Louis Medical Scientist Training Program (NIH grant T32GM007200), the Washington University in St. Louis Institute of Clinical and Translational Sciences (NIH grants UL1TR000448, TL1TR000449), the Washington University Diabetic Cardiovascular Disease Center, the American Federation for Aging Research, and the VitreoRetinal Surgery Foundation. The authors acknowledge Douglas Cox for technical assistance, Dr. David Beebe for advice regarding Seahorse experiments, Dr. Kevin Yarasheski at the Washington University Metabolomics Core for assistance with analyzing retinal samples, and Dr. Raul Mostoslavsky for providing resources. R.S.A. is a co-founder of Metro Midwest Biotech, which is developing NMN-based therapeutics. Publisher Copyright: {\textcopyright} 2016 The Author(s)",
year = "2016",
month = sep,
day = "27",
doi = "10.1016/j.celrep.2016.08.073",
language = "English",
volume = "17",
pages = "69--85",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "1",
}
