Why is NMNAT Protective against Neuronal Cell Death and Axon Degeneration, but Inhibitory of Axon Regeneration?

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.

A photo-switchable assay system for dendrite degeneration and repair in Drosophila melanogaster

“…Candidate genes can also exert opposite functions during the degeneration and repair processes. Studies have started to show that some candidate genes, including nicotinamide mononucleotide adenylyltransferase and Dual leucine zipper kinase, that were found to protect neurons from degeneration and cell death may prohibit the capacity to regenerate ( 50 , 51 ). Notably, Wld S mice also exhibit poor axon regeneration with delayed axon degeneration ( 52 ).…”

Insights into nervous system repair from the fruit fly

“…Yet, NMNAT’s rescue of the distal axon creates a significant obstacle for regrowth of the proximal axon that requires a clearance of debris [ 32 , 58 ]. It is thought that NMNATs may also indirectly act to inhibit PI3K-mTORC regenerative signaling [ 59 ]. An example of the biphasic role of NMNATs in response to axon injury is shown during ddaE sensory neuron axotomy, in which dNmnat degradation is required for normal WD to occur whereas its overexpression reduces the regrowth of the proximal axon stump normally observed [ 58 ].…”

Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration

“…Other mammalian NMNAT isoforms such as NMNAT2 (located in the Golgi apparatus and cytosol) and NMNAT3 (located in the mitochondria) are also reported to exert axonal protection in different neuronal models [71]. Kitaoka and colleagues evaluated the protective effect of NMNAT3 overexpression on optic nerve axonal protection in two different mouse models of glaucoma (the TNF injection model and the hypertensive glaucoma model).…”