More Than Meets the Eye: Roles of NAD-synthase NMNAT1 in Retinal Development and Metabolism

David Sokolov*, Joseph Murphy, Emily Sechrest, Yekai Wang, Jianhai Du, Saravanan Kolandaivelu, Department of Ophthalmology, West Virginia University, Morgantown, WV, 26505

Field (Broad Category): Biology (Biological & Biochemical Sciences) 

Student’s Major: Biology, Mathematics 

Mutations in the NAD-synthesizing protein nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) are linked to Leber’s congenital amaurosis, a severe blinding disease which is the leading cause of inherited blindness in children. Strikingly, these mutations in NMNAT1—which is present in all cells of the body— often result in blindness without other detectable symptoms, suggesting an especially crucial role for this protein in the retina of the eye. Despite this, the specific functions of NMNAT—especially in the retina—are not well described. To better understand these functions, we generated and characterized a mouse model with retinal-specific deletion of the NMNAT1 gene. Our results indicate that retina lacking NMNAT1 experience very early and severe retinal degeneration, starting at birth and complete by one month of age. Large scale analyses of retinal metabolism and gene expression reveal that NMNAT1-null retina experience defects in cell-energy pathways including glycolysis, as well as specific problems with proper gene regulation. Specifically, our RNA-sequencing results implicate NMNAT1 in the proper development of cilia— the long, light-sensing structures which some retinal cells use to detect light signals. Overall, our findings show that NMNAT1 is crucial for the late-stage development of the retina, most likely due to NMNAT1’s central role in retinal metabolism and gene regulation. Our results contribute to an understanding of NMNAT1’s normal function in the retina, and its dysfunction in blinding diseases like LCA. 

Funding: Henry Hurlbutt Research Award (to DS) 

Program/mechanism supporting research/creative efforts: Biology 486 capstone