1. ¹The Babraham Institute, Cambridge CB2 4AT, UK
2. ²Emory Center for Neurodegenerative Disease, 615 Michael Street, Atlanta, GA 303222, USA
3. ³Institute of Biochemical Biotechnologies, University of Ancona, Via Ranieri, Ancona 60131, Italy

Correspondence: MP Coleman, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK. Tel: +44 1223 496315; Fax: +44 1223 496348; E-mail: michael.coleman@bbsrc.ac.uk; Professor JD Glass, Emory Center for Neurodegenerative Disease, Whitehead Biomedical Research Building, 5th Floor, 615 Michael Street, Mailstop 1941007001, Atlanta, GA 30322, USA. Tel: +1 404 727 3507; Fax: +1 404 727 3278; E-mail: jglas03@emory.edu

⁴These authors contributed equally to this work

⁵These authors contributed equally to each other to this work

Received 26 August 2005; Revised 10 March 2006; Accepted 16 March 2006; Published online 28 April 2006.

Abstract

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.