Nuclear NAD⁺-biosynthetic enzyme NMNAT1 facilitates survival of developing retinal neurons

Abstract

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 extra-nuclear metabolic disruptions to retinal central carbon metabolism, purine nucleotide synthesis, and amino acid pathways. Furthermore, large-scale transcriptomics reveals dysregulation of a collection of photoreceptor and synapse-specific genes in NMNAT1 knockout retinas prior to detectable morphological or metabolic alterations. Collectively, our study furthers understanding of subcellular NAD+ metabolism in vision, reveals previously unrecognized complexity in NMNAT1-associated retinal degeneration, and suggests a yet-undescribed role for NMNAT1 in genetic regulation of photoreceptor terminal differentiation.

Identification and characterization of early human photoreceptor states and cell-state-specific retinoblastoma-related features

“…Genes upregulated in the LR cluster were enriched for photoreceptor and light sensing gene ontologies (Figure S1K) including spectrin binding, likely relating to proteins that control photoreceptor polarity and synapse formation 29,30 , and purine biosynthesis and ribonucleotide metabolic processes, potentially related to the developing photoreceptors' high NAD+ requirements 31 .…”