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

Fine needle aspiration of human lymph nodes reveals cell populations and soluble interactors pivotal to immunological priming

“…Several of the proteins specifically detected in the LN aspirates of all three participants (Fig. 5F) include TREM2, ADAM22, NTF3, and NMNAT1 (Table S5), all of which have well‐documented roles in neuronal and microglial function [33–36]. As the cervical LNs sampled are thought to drain the dural sinuses [4], we postulated that the detection of these proteins in LN aspirates would suggest sampling of lymphatic‐associated material.…”

Fine needle aspiration of human lymph nodes reveals cell populations and soluble interactors pivotal to immunological priming

“…Several of the proteins specifically detected in the LN aspirates of all three participants (Figure 5F) include TREM2, ADAM22, NTF3, and NMNAT1 (Supplemental Table 3), all of which have well-documented roles in neuronal and microglial function (32–35). As the cervical LNs sampled are thought to drain the dural sinuses (4), we postulated that detection of these proteins in LN aspirates would suggest sampling of lymphatic-associated material.…”

Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair

“…Moreover, as highlighted above, CASP2-dependent cell death is activated by low NADPH levels, which is found in Pde6b rd1 mice and associated with retinal degeneration ( Venkatesh et al, 2015 ). In this regard, it is of interest that deleting Nmnat1 (NAD + synthase nicotinamide mononucleotide adenylyltransferase-1), which regulates the formation of NAD + to shuttle electrons, in retinal progenitor cells created with a Six3-Cre driver leads to defects in photoreceptor maturation and survival, with multiple cell death pathways activated (i.e., apoptosis, pyroptosis, necroptosis) ( Sokolov et al, 2021 ). Interestingly, there is a striking disruption of multiple retinal metabolites (39/112 metabolites de-regulated, as determined by LC-MS/MS), which taken together reveal defects in central carbon metabolism, including glycolytic flux ( Sokolov et al, 2021 ).…”