title: Endogenous Nmnat2 is an essential survival factor for maintenance of healthy axons.
abstract: The molecular triggers for axon degeneration remain unknown. We identify endogenous Nmnat2 as a labile axon survival factor whose constant replenishment by anterograde axonal transport is a limiting factor for axon survival. Specific depletion of Nmnat2 is sufficient to induce Wallerian-like degeneration of uninjured axons which endogenous Nmnat1 and Nmnat3 cannot prevent. Nmnat2 is by far the most labile Nmnat isoform and is depleted in distal stumps of injured neurites before Wallerian degeneration begins. Nmnat2 turnover is equally rapid in injured Wld(S) neurites, despite delayed neurite degeneration, showing it is not a consequence of degeneration and also that Wld(S) does not stabilize Nmnat2. Depletion of Nmnat2 below a threshold level is necessary for axon degeneration since exogenous Nmnat2 can protect injured neurites when expressed at high enough levels to overcome its short half-life. Furthermore, proteasome inhibition slows both Nmnat2 turnover and neurite degeneration. We conclude that endogenous Nmnat2 prevents spontaneous degeneration of healthy axons and propose that, when present, the more long-lived, functionally related Wld(S) protein substitutes for Nmnat2 loss after axon injury. Endogenous Nmnat2 represents an exciting new therapeutic target for axonal disorders.
authors.affiliation: The Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gilley
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000235:genetics; D016501:Neurites / Q000378:metabolism / Q000502:physiology / Q000648:ultrastructure; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic
chemical_list: D009612:Nicotinamide-Nucleotide Adenylyltransferase