title: Axonal trafficking of NMNAT2 and its roles in axon growth and survival in vivo.
abstract: The NAD-synthesizing enzyme NMNAT2 is critical for axon survival in primary culture and its depletion may contribute to axon degeneration in a variety of neurodegenerative disorders. Here we discuss several recent reports from our laboratory that establish a critical role for NMNAT2 in axon growth in vivo in mice and shed light on the delivery and turnover of this survival factor in axons. In the absence of NMNAT2, axons fail to extend more than a short distance beyond the cell body during embryonic development, implying a requirement for NMNAT2 in axon maintenance even during development. Furthermore, we highlight findings regarding the bidirectional trafficking of NMNAT2 in axons on a vesicle population that undergoes fast axonal transport in primary culture neurites and in mouse sciatic nerve axons in vivo. Surprisingly, loss of vesicle association boosts the axon protective capacity of NMNAT2, an effect that is at least partially mediated by a longer protein half-life of cytosolic NMNAT2 variants. Analysis of wild-type and variant NMNAT2 in mouse sciatic nerves and Drosophila olfactory receptor neuron axons supports the existence of a similar mechanism in vivo, highlighting the potential for regulation of NMNAT2 stability and turnover as a mechanism to modulate axon degeneration in vivo.
authors.affiliation: The Babraham Institute; Babraham Research Campus; Cambridge, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Milde
authors.affiliation: The Babraham Institute; Babraham Research Campus; Cambridge, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gilley
authors.affiliation: The Babraham Institute; Babraham Research Campus; Cambridge, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology*; D017353:Gene Deletion; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D016501:Neurites / Q000473:pathology*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology*; D013347:Subcellular Fractions / Q000378:metabolism*; D014855:Wallerian Degeneration / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D009612:Nicotinamide-Nucleotide Adenylyltransferase
keywords: NMNAT2; Wallerian degeneration; axon growth; axon survival; axonal transport; neurodegeneration; palmitoylation; ubiquitin proteasome