Abstract
Nicotinamide mononucleotide adenylyltransferase (NMNAT), a key enzyme for NAD+ synthesis, is well known for its activity in neuronal survival and attenuation of Wallerian degeneration. Recent investigations in invertebrate models have, however, revealed that NMNAT activity negatively impacts upon axon regeneration. Overexpression of Nmnat in laser-severed Drosophila sensory neurons reduced axon regeneration, while axon regeneration was enhanced in injured mechanosensory axons in C. elegans nmat-2 null mutants. These diametrically opposite effects of NMNAT orthologues on neuroprotection and axon regeneration appear counterintuitive as there are many examples of neuroprotective factors that also promote neurite outgrowth, and enhanced neuronal survival would logically facilitate regeneration. We suggest here that while NMNAT activity and NAD+ production activate neuroprotective mechanisms such as SIRT1-mediated deacetylation, the same mechanisms may also activate a key axonal regeneration inhibitor, namely phosphatase and tensin homolog (PTEN). SIRT1 is known to deacetylate and activate PTEN which could, in turn, suppress PI3 kinase–mTORC1-mediated induction of localized axonal protein translation, an important process that determines successful regeneration. Strategic tuning of Nmnat activity and NAD+ production in axotomized neurons may thus be necessary to promote initial survival without inhibiting subsequent regeneration.
Highlights
Nicotinamide mononucleotide adenylyltransferase (NMNAT) is an evolutionarily conserved rate-limiting enzyme that catalyzes the salvage pathway biosynthesis of the essential coenzyme nicotinamide adenine dinucleotide (NAD+ ) from ATP and nicotinamide mononucleotide (NMN) [1].Humans have three nicotinamide mononucleotide adenylyltransferase (NMNAT) paralogues, where NMNAT1 and NMNAT3(mitochondrial and cytoplasmic depending on splice variant) are more ubiquitously expressed, while NMNT2 is enriched in brain [2,3,4]
Loss of NMNAT2 in mice resulted in perinatal lethality with severe defects in peripheral nerves and regions of the central nervous system (CNS) [9]
As far as neuronal injury is concerned, a important activity of NMNAT is its attenuation of Wallerian degeneration (WD) [42]. This was first demonstrated by mice with a remarkable post-injury retardation in WD, where the underlying protective mutant gene Wallerian degeneration slow (Wlds ) encodes a fusion protein of the N-terminal fragment of ubiquitination factor E4B (Ube4b) to NMNAT [43]
Summary
Nicotinamide mononucleotide adenylyltransferase (NMNAT) is an evolutionarily conserved rate-limiting enzyme that catalyzes the salvage pathway biosynthesis of the essential coenzyme nicotinamide adenine dinucleotide (NAD+ ) from ATP and nicotinamide mononucleotide (NMN) [1]. NMNAT is a stress- and injury-induced protein [5,6] and plays a critical role in the maintenance of neuronal survival and health [3,7,8]. As far as neuronal injury is concerned, a important activity of NMNAT is its attenuation of Wallerian degeneration (WD) [42]. This was first demonstrated by mice with a remarkable post-injury retardation in WD, where the underlying protective mutant gene Wallerian degeneration slow (Wlds ) encodes a fusion protein of the N-terminal fragment of ubiquitination factor E4B (Ube4b) to NMNAT [43]. NMNAT1 has been shown to inhibit axon degeneration by directly blocking injury-induced and SARM1-dependent NAD+ destruction [55]. NMNAT could exerts its neuroprotective functions in different ways which could potentially compliment, or even reinforce one other
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