The Kolandaivelu Lab Uncover the Mechanism Behind a Protein Associated with Severe Blinding Diseases

Research in Dr. Kolandaivelu’s lab focuses on studying the intricate biology of the retina and using that knowledge to better understand blinding diseases which affect millions of people globally. Recently, his lab published an article in eLife journal of a multi-year project focused on studying a specific protein in the retina, called NMNAT1.

NMNAT1 is an enzyme which produces NAD⁺, a crucial molecule which enables cells to generate energy, regulate their genomes, and respond to their environments. Interestingly, even though the NMNAT1 protein is present in almost every cell of the body, mutations in this protein cause a devastating blinding disease “Leber’s Congenital Amaurosis” (LCA), which leads to complete vision loss early in life and has no effective treatments. Why mutations in this ubiquitous protein cause retina-specific disease is still puzzling researchers worldwide, but recent results from the Kolandaivelu laboratory may provide important clues for understanding this protein and its function in the retina.

To tackle these questions, a research team led by Dr. Kolandaivelu and first author David Sokolov, an undergraduate student from Kolandaivelu lab, removed NMNAT1 from the retinas of developing mice and used a combination of molecular, cell-biological, and genomic approaches to examine the consequences of losing this enzyme to retinal health. They found that losing NMNAT1 and the NAD⁺ that it causes specific changes to retinal metabolism and affects different retinal cell types to varying degrees. Among the retinal cell types, they examined, photoreceptors, the cells in the retina responsible for sensing light, were particularly affected in the absence of NMNAT1. Using the advantages of their approach over previous studies from other groups, the Kolandaivelu team found that NMNAT1 is crucial for the proper development of these photoreceptor cells a function for retinal NMNAT1, which had not previously been shown.

Although scientists are increasingly appreciating the important roles of NAD⁺ in gene regulation and development, the Kolandaivelu team’s findings concerning retinal NMNAT1 provide important steps forward in our understanding of these processes and lay the groundwork for follow-up studies from the Kolandaivelu Laboratory and others. The hope is that a better understanding of exactly what goes wrong in the retina when NMNAT1 is mutated can enable the development of effective treatments for NMNAT1-linked blinding diseases, all the while helping us to better understand the fundamental biology of NAD⁺ and its many important roles in the cell.