title: Wld S protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice.
abstract: 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.
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, England, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Conforti
authors.forename: Anna
authors.initials: A
authors.lastname: Wilbrey
authors.forename: Giacomo
authors.initials: G
authors.lastname: Morreale
authors.forename: Lucie
authors.initials: L
authors.lastname: Janeckova
authors.forename: Bogdan
authors.initials: B
authors.lastname: Beirowski
authors.forename: Robert
authors.initials: R
authors.lastname: Adalbert
authors.forename: Francesca
authors.initials: F
authors.lastname: Mazzola
authors.forename: Michele
authors.initials: M
authors.lastname: Di Stefano
authors.forename: Robert
authors.initials: R
authors.lastname: Hartley
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Babetto
authors.forename: Trevor
authors.initials: T
authors.lastname: Smith
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gilley
authors.forename: Richard A
authors.initials: RA
authors.lastname: Billington
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.forename: Richard R
authors.initials: RR
authors.lastname: Ribchester
authors.forename: Giulio
authors.initials: G
authors.lastname: Magni
authors.forename: Michael
authors.initials: M
authors.lastname: Coleman
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C442580:Wld protein, mouse; C510972:Nmnat1 protein, mouse