Nature Neuroscience
4, 1199 - 1206 (2001)
Published online: 19 November 2001; | doi:10.1038/nn770
Wallerian degeneration of injured axons and synapses is delayed by a Ube4b/Nmnat chimeric geneTill G.A. Mack1, Michael Reiner2, Bogdan Beirowski2, Weiqian Mi1, Monica Emanuelli3, Diana Wagner1, Derek Thomson4, Tom Gillingwater4, Felipe Court4, Laura Conforti5, F. Shama Fernando6, Andrea Tarlton7, Christian Andressen2, Klaus Addicks2, Giulio Magni3, Richard R. Ribchester4, V. Hugh Perry8
& Michael P. Coleman1, 61
Center for Molecular Medicine (ZMMK) and Institute for Genetics, University of Cologne, Zuelpicher Strasse 47, D-50674 Cologne, Germany
2
Department of Anatomy I, University of Cologne, Joseph-Stelzmann Strasse 9, D-50931 Cologne, Germany
3
Institute of Biochemistry, University of Ancona, Via Ranieri, 60131 Ancona, Italy
4
Department of Neuroscience, University of Edinburgh, 1 George Square, Edinburgh, EH8 9JZ, UK
5
Molecular Neurobiology Laboratory, Mario Negri Pharmaceutical Research Institute, Via Eritrea, 62, 20157 Milan, Italy
6
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
7
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
8
School of Biological Sciences, University of Southampton, Biomedical Sciences Building, Southampton, SO16 7PX, UK
Correspondence should be addressed to Michael P. Coleman michael.coleman@uni-koeln.deAxons and their synapses distal to an injury undergo rapid Wallerian degeneration, but axons in the C57BL/Wld
S mouse are protected. The degenerative and protective mechanisms are unknown. We identified the protective gene, which encodes an N-terminal fragment of ubiquitination factor E4B (Ube4b) fused to nicotinamide mononucleotide adenylyltransferase (Nmnat), and showed that it confers a dose-dependent block of Wallerian degeneration. Transected distal axons survived for two weeks, and neuromuscular junctions were also protected. Surprisingly, the Wld protein was located predominantly in the nucleus, indicating an indirect protective mechanism. Nmnat enzyme activity, but not NAD+ content, was increased fourfold in Wld
S tissues. Thus, axon protection is likely to be mediated by altered ubiquitination or pyridine nucleotide metabolism.
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