Low levels of NMNAT2 compromise axon development and survival

Abstract

NMNAT2 is an endogenous axon maintenance factor that preserves axon health by blocking Wallerian-like axon degeneration. Mice lacking NMNAT2 die at birth with severe axon defects in both the PNS and CNS so a complete absence of NMNAT2 in humans is likely to be similarly harmful, but probably rare. However, there is evidence of widespread natural variation in human NMNAT2 mRNA expression so it is important to establish whether reduced levels of NMNAT2 have consequences that impact health. Whilst mice that express reduced levels of NMNAT2, either those heterozygous for a silenced Nmnat2 allele, or compound heterozygous for one silenced and one partially silenced Nmnat2 allele, remain overtly normal into old age, we now report that Nmnat2 compound heterozygote mice present with early and age-dependent peripheral nerve axon defects. Compound heterozygote mice already have reduced numbers of myelinated sensory axons at 1.5 months and lose more axons, likely motor axons, between 18 and 24 months and, crucially, these changes correlate with early temperature insensitivity and a later-onset decline in motor performance. Slower neurite outgrowth and increased sensitivity to axonal stress are also evident in primary cultures of Nmnat2 compound heterozygote superior cervical ganglion neurons. These data reveal that reducing NMNAT2 levels below a particular threshold compromises the development of peripheral axons and increases their vulnerability to stresses. We discuss the implications for human neurological phenotypes where axons are longer and have to be maintained over a much longer lifespan.

Homozygous NMNAT2 mutation in sisters with polyneuropathy and erythromelalgia

“…The accompanying paper (Lukacs et al) reports a more severe and lethal phenotype associated with near-complete biallelic loss-of-function of NMNAT2. In common with the T94M phenotype, this is consistent with an axon loss phenotype (or failure of axon growth) affecting multiple neuron types, as also observed in both the complete null and knockdown mice 6,18,28 . The severity of the two human phenotypes correlates well with the degree of loss-of-function with the corresponding models in mice.…”

“…All previous data on NMNAT2 mutant phenotypes come from mouse studies where expression is either reduced or ablated. The T94M mutation only partly disrupts the function of NMNAT2, so T94M homozygosity in the patients is arguably more similar to mice with heterozygous levels (~50%) or sub-heterozygous levels (~30%) of NMNAT2, which are viable into old age, than to mice homozygous for a silenced allele where a failure of nerve growth precludes survival 6,28 . Intriguingly, there are strong parallels between the patients described here and mice with sub-heterozygous levels of NMNAT2.…”

“…Intriguingly, there are strong parallels between the patients described here and mice with sub-heterozygous levels of NMNAT2. Specifically, both have a clear, early-onset sensory phenotype involving loss of myelinated sensory axons in peripheral nerves and altered temperature sensation 28 . The absence of this phenotype in mice with heterozygous NMNAT2 levels outwardly suggests that episodes of erythromelalgia in the patients requires reduction in NMNAT2 activity to sub-heterozygous levels.…”

Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration

“…We have recently reported that lowering the expression of NMNAT2 increases axonal 135 vulnerability to several stresses (Gilley et al, 2019). To test whether lowering NMNAT2 136 expression impairs the ability to withstand mitochondrial impairment, SCG neurons 137 from mice with around 60% (Nmnat2 +/gtE ) and 30% (Nmnat2 gtBay/gtE ) of wild type 138…”

Potential Therapeutic Benefit of NAD+ Supplementation for Glaucoma and Age-Related Macular Degeneration

“…NMNAT2 localizes to the Golgi and cytosolic compartments and localized exclusively to neurons and hair follicles [ 28 ]. In neurons, NMNAT2 plays a pivotal role in axon development and survival [ 29 , 30 , 31 ] and its depletion can trigger Wallerian degeneration [ 32 , 33 ]. While the role of NAD + in balancing cellular homeostasis is evolutionally conserved [ 34 ], only three pathways that lead to NAD + synthesis have been described (in mammalian cells, the core focus of this review) [ 35 ].…”