Disruption of nicotinamide adenine dinucleotide (NAD+) biosynthesis could be an early step in retinal dysfunction, according to a new study conducted in mice.
Retinal dysfunction results from many diseases, such as diabetic retinopathy and age-related macular degeneration; however, the shared pathological mechanisms are unclear. Mutations affecting the biosynthesis of NAD+, an important coenzyme and electron carrier, have previously been associated with inherited blinding diseases. Jonathan Lin and colleagues, therefore, investigated whether decreased levels of NAD+ lead to retinal degeneration.
The team generated mice that lacked nicotinamide phosphoribosyltransferase (the rate-limiting enzyme in the dominant mammalian pathway of NAD+ synthesis, which is encoded by Nampt), specifically within photoreceptors. These Nampt-deficient mice had retinal atrophy by 6 weeks of age and disrupted electroretinography readings, both of which could be rescued by injection of the NAD+ precursor nicotinamide mononucleotide. Interestingly, several mouse models of retinal degeneration, including streptozotocin-induced diabetic retinopathy and light-induced retinal dysfunction, had lower retinal NAD+ levels than healthy controls.
The team also examined cultured photoreceptor-like cells treated with the Nampt inhibitor FK866, and detected a decreased reductive capacity compared with untreated cells. This effect was not seen in retinal pigment epithelium cells, suggesting a distinct susceptibility in photoreceptor cells. Furthermore, the FK866-treated photoreceptor cells exhibited hyperacetylation of mitochondrial proteins, potentially resulting from a reduction in SIRT3 activity, which could be an important contributor to mitochondrial dysfunction.
“NAD+ intermediates may have therapeutic efficacy against a broad range of retinal diseases,” concludes Lin. “We are very excited about these translational possibilities.”
References
Lin, J. B. et al. NAMPT-mediated NAD+ biosynthesis is essential for vision in mice. Cell Rep. http://dx.doi.org/10.1016/j.celrep.2016.08.073 (2016)
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Ridler, C. Nampt deletion blinds mice. Nat Rev Endocrinol 12, 687 (2016). https://doi.org/10.1038/nrendo.2016.174
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DOI: https://doi.org/10.1038/nrendo.2016.174