Wld S protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice.
The slow Wallerian degeneration (Wld(S)) protein protects injured axons from degeneration. This unusual chimeric protein fuses a 70-amino acid N-terminal sequence from the Ube4b multiubiquitination factor with the nicotinamide adenine dinucleotide-synthesizing enzyme nicotinamide mononucleotide adenylyl transferase 1. The requirement for these components and the mechanism of Wld(S)-mediated neuroprotection remain highly controversial. The Ube4b domain is necessary for the protective phenotype in mice, but precisely which sequence is essential and why are unclear. Binding to the AAA adenosine triphosphatase valosin-containing protein (VCP)/p97 is the only known biochemical property of the Ube4b domain. Using an in vivo approach, we show that removing the VCP-binding sequence abolishes axon protection. Replacing the Wld(S) VCP-binding domain with an alternative ataxin-3-derived VCP-binding sequence restores its protective function. Enzyme-dead Wld(S) is unable to delay Wallerian degeneration in mice. Thus, neither domain is effective without the function of the other. Wld(S) requires both of its components to protect axons from degeneration.
Conforti
Laura
L
Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, England, UK.
Wilbrey
Anna
A
Morreale
Giacomo
G
Janeckova
Lucie
L
Beirowski
Bogdan
B
Adalbert
Robert
R
Mazzola
Francesca
F
Di Stefano
Michele
M
Hartley
Robert
R
Babetto
Elisabetta
E
Smith
Trevor
T
Gilley
Jonathan
J
Billington
Richard A
RA
Genazzani
Armando A
AA
Ribchester
Richard R
RR
Magni
Giulio
G
Coleman
Michael
M
D000818:Animals; D001369:Axons / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C442580:Wld protein, mouse; C510972:Nmnat1 protein, mouse