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WldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice

2009; Rockefeller University Press; Volume: 184; Issue: 4 Linguagem: Inglês

10.1083/jcb.200807175

1540-8140

Laura Conforti, Anna Wilbrey, Giacomo Morreale, Lucie Janečková, Bogdan Beirowski, Róbert Adalbert, Francesca Mazzola, M. Di Stefano, Robert W. Hartley, Elisabetta Babetto, Trevor Smith, Jonathan Gilley, Richard Billington, Armando A. Genazzani, Richard R. Ribchester, Giulio Magni, Michael P. Coleman,

Nerve injury and regeneration

The slow Wallerian degeneration (WldS) 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 WldS-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 WldS VCP-binding domain with an alternative ataxin-3–derived VCP-binding sequence restores its protective function. Enzyme-dead WldS is unable to delay Wallerian degeneration in mice. Thus, neither domain is effective without the function of the other. WldS requires both of its components to protect axons from degeneration.