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Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD + salvage pathway. Our previous study demonstrated that deletion of NAMPT gene in projection neurons using Thy1-NAMPT -/- conditional knockout (cKO) mice causes neuronal degeneration, muscle atrophy, neuromuscular junction abnormalities, paralysis and eventually death. Here we conducted a combined metabolomic and transcriptional profiling study in vivo in an attempt to further investigate the mechanism of neuronal degeneration at metabolite and mRNA levels after NAMPT deletion. Here using steady-state metabolomics, we demonstrate that deletion of NAMPT causes a significant decrease of NAD + metabolome and bioenergetics, a buildup of metabolic intermediates upstream of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in glycolysis, and an increase of oxidative stress. RNA-seq shows that NAMPT deletion leads to the increase of mRNA levels of enzymes in NAD metabolism, in particular PARP family of NAD + consumption enzymes, as well as glycolytic genes Glut1, Hk2 and PFBFK3 before GAPDH. GO, KEGG and GSEA analyses show the activations of apoptosis, inflammation and immune responsive pathways and the inhibition of neuronal/synaptic function in the cKO mice. The current study suggests that increased oxidative stress, apoptosis and neuroinflammation contribute to neurodegeneration and mouse death as a direct consequence of bioenergetic stress after NAMPT deletion.

journal of cerebral blood flow and metabolism

Metabolomic and transcriptional profiling reveals bioenergetic stress and activation of cell death and inflammatory pathways <i>in vivo</i> after neuronal deletion of NAMPT

Metabolomic and transcriptional profiling reveals bioenergetic stress and activation of cell death and inflammatory pathways in vivo after neuronal deletion of NAMPT