Eyeworld

EW RETINA 126 by Liz Hillman EyeWorld Staff Writer Finding could someday lead to treatment to prevent vision loss A ge-related macular degen- eration. Retinitis pigmen- tosa. Leber congenital amaurosis. What do these diseas- es have in common? Photoreceptor death leading toward vision loss and Researchers identify possible unifying pathway behind many retinal diseases March 2017 Fundus images (left) mice lacking Nampt with severe retinal degeneration at 6 weeks compared to normal mice. Retinal sections (right) show a reduced outer nuclear layer thickness and secondary retinal degeneration in mice lacking Nampt at 6 weeks compared to normal mice. Source (all): Cell Reports via CC BY 4.0 Research highlight continued on page 128 blindness—and the list of other reti- nal diseases with a similar endpoint could go on. What leads to damage and dysfunction of these cells differs depending on the disease, but one study suggests a unifying, under- lying pathway that could connect them all. Recent research published in Cell Reports showed how disruption of a metabolic pathway led to dam- age of rods and cones and photore- ceptor death. 1 What's more, scien- tists were able to "rescue" these cells, suggesting a possible therapy for patients with many different types of retinal disorders in the future. Jonathan Lin, Department of Ophthalmology and Visual Scienc- es, Washington University School of Medicine, St. Louis, and MD/ PhD candidate in the neuroscience graduate program, led research that disrupted the biosynthesis of the essential coenzyme nicotinamide adenine dinucleotide (NAD+) in a mouse model. According to the study, previous research has de- scribed the different processes that involve NAD+, including metabo- lism, aging, and neurodegeneration. The role of NAD+ in retinal degen- eration, however, was "relatively unexplored." "It seems clear that the retina photoreceptors have enormous energy requirements. We thought metabolism might be a key unifying factor that's identified in different diseases," Mr. Lin, first author of the study, said. "Along those lines, there are also recent reports that Leber congenital amaurosis, which is a blinding disease in children, can be caused by mutations of this pro- tein called NMNAT1. This is a key protein in the NAD+ pathway. Since there have been a lot of reports of the importance of NAD+ in other neurodegenerative diseases… we wanted to understand whether this NAD+ pathway is also important in retinal degeneration." The researchers created condi- tional knockout mice that didn't have nicotinamide phosphoribos- yltransferase (Nampt)—a catalyst in the most common NAD+ produc- tion pathway in mammals. In other words, they created mice that did not produce normal levels of NAD+ by deleting the gene for this in rod cells. The researchers observed reduced Nampt gene expression and a 25% reduction in retinal NAD+ at 3 weeks. In rods specifically, a 45% reduction in NAD+ levels was ob- served compared to normal mice. By 6 weeks, "massive atrophy of the neurosensory retina, vascular attenuation with pigment mottling, and atrophy of the underlying reti- nal pigment epithelium (RPE) cells" was observed in the experimental mice group. A disruption in visual function was also observed. There were similar results in mice with the Nampt deletion in cone cells. "To us, it was remarkable how dramatic the degeneration was. By 6 weeks, there is almost a complete ab- sence of that photoreceptor layer," Mr. Lin said. "It was remarkable that 500 µm 100 µm

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