NAD(+) and axon degeneration revisited: Nmnat1 cannot substitute for Wld(S) to delay Wallerian degeneration.
The slow Wallerian degeneration protein (Wld(S)), a fusion protein incorporating full-length nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), delays axon degeneration caused by injury, toxins and genetic mutation. Nmnat1 overexpression is reported to protect axons in vitro, but its effect in vivo and its potency remain unclear. We generated Nmnat1-overexpressing transgenic mice whose Nmnat activities closely match that of Wld(S) mice. Nmnat1 overexpression in five lines of transgenic mice failed to delay Wallerian degeneration in transected sciatic nerves in contrast to Wld(S) mice where nearly all axons were protected. Transected neurites in Nmnat1 transgenic dorsal root ganglion explant cultures also degenerated rapidly. The delay in vincristine-induced neurite degeneration following lentiviral overexpression of Nmnat1 was significantly less potent than for Wld(S), and lentiviral overexpressed enzyme-dead Wld(S) still displayed residual neurite protection. Thus, Nmnat1 is significantly weaker than Wld(S) at protecting axons against traumatic or toxic injury in vitro, and has no detectable effect in vivo. The full protective effect of Wld(S) requires more N-terminal sequences of the protein.
Conforti
L
L
The Babraham Institute, Cambridge CB2 4AT, UK.
Fang
G
G
Beirowski
B
B
Wang
M S
MS
Sorci
L
L
Asress
S
S
Adalbert
R
R
Silva
A
A
Bridge
K
K
Huang
X P
XP
Magni
G
G
Glass
J D
JD
Coleman
M P
MP
D000818:Animals; D001369:Axons / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009243:NAD / Q000378:metabolism* / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000235:genetics / Q000502:physiology*; D017354:Point Mutation; D000077185:Resveratrol; D020426:Sciatic Neuropathy / Q000139:chemically induced / Q000517:prevention & control; D013267:Stilbenes / Q000494:pharmacology; D014855:Wallerian Degeneration / Q000517:prevention & control*
D009419:Nerve Tissue Proteins; D013267:Stilbenes; C442580:Wld protein, mouse; D009243:NAD; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C510972:Nmnat1 protein, mouse; D000077185:Resveratrol