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

¹ Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, England, UK
² Istituto di Biotecnologie Biochimiche, Università Politecnica delle Marche, 60131 Ancona, Italy
³ Centre for Neuroscience Research, University of Edinburgh, Edinburgh EH8 9JZ, Scotland, UK
⁴ Dipartimento di Scienze Chimiche, Alimentari, Farmaceutiche, e Farmacologiche and ⁵ Drug and Food Biotechnology Center, Università del Piemonte Orientale, 28100 Novara, Italy

Correspondence to Michael Coleman: michael.coleman{at}bbsrc.ac.uk

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.

© 2009 Conforti et al.
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