Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates development and early survival of retinal neurons

Despite mounting evidence that the mammalian retina is exceptionally reliant on proper NAD(+) homeostasis for health and function, the specific roles of subcellular NAD(+) pools in retinal development, maintenance, and disease remain obscure. Here, we show that deletion of the nuclear-localized NAD(+) synthase nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1) in the developing murine retina causes early and severe degeneration of photoreceptors and select inner retinal neurons via multiple distinct cell death pathways. This severe phenotype is associated with disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, transcriptomic and immunostaining approaches reveal dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration and suggests a yet-undescribed role for NMNAT1 in gene regulation during photoreceptor terminal differentiation.

Automated summary

This study reveals the previously unrecognized complexity in NMNAT1-associated retinal degeneration, indicating a potential role for NMNAT1 in gene regulation during photoreceptor terminal differentiation. Deletion of nuclear-localized NAD(+) synthase NMNAT1 in developing murine retina leads to early and severe degeneration of photoreceptors and inner retinal neurons, associated with disruptions in central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Dysregulation of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas is observed prior to detectable morphological or metabolic alterations.