International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)


THE WLD GENE: A UNIQUE NEUROPROTECTIVE FACTOR FOR AXONS

Michael Coleman
University of Cologne
Institute for Genetics & Center for Molecular Medicine (ZMMK),
Zuelpicher Strasse 47
Cologne D-50674 Germany

Co-Authors: 1)Mack TGA, 1)Reiner M, 1)Beirowski B, 1)Mi W, 2)Emanuelli M, 1)Wagner D, 3)Thomson D, 3)Gillingwater T, 4)Conforti L, 5)Fernando FS, 5)Tarlton A, 1)Addicks K, 2)Magni G, 6)Perry VH, 3)Ribchester RR
Institutions: 1)University of Cologne, 2)University of Ancona, 3)University of Edinburgh, 4)Mario Negri Institute, Milan, 5)University of Oxford, 6)University of Southampton

The Wld gene: a unique neuroprotective factor for axons

Axon degeneration in both injury and disease (Wallerian degeneration) is greatly delayed by a dominant mutation in the C57BL/WldS mouse. Here we identify the protective gene by reproducing the WldS phenotype in transgenic mice. We confer a dosage-dependent block of Wallerian degeneration by expressing an in-frame fusion protein of Ubiquitination factor E4B (Ube4b) and Nicotinamide mononucleotide adenylyltransferase (Nmnat). Five days after transection, up to 96% of distal axons and 93% of neuromuscular junctions were structurally and functionally preserved in transgenic mice, compared to none in wild-type mice. 70% of axons survive for at least 14 days. Thus, degeneration of axotomised nerves can be prevented. Nmnat enzyme activity is present in the protective protein and increases four-fold in WldS tissues without altering NAD+ content. These data indicate that ubiquitination or pyridine nucleotide metabolism underlies Wallerian degeneration and axon protection.

Degeneration of the axon, the largest compartment in many neurons, has been inexplicably neglected in studies of neurodegenerative disease. Studies showing that the WldS mutation also protects from peripheral neuropathy (Samsam, M. and Martini R., in preparation) and motoneuron disease (Ferri, A. and Kato, A., personal communication) indicate that the Wld gene fills an important gap in potential therapeutic strategies. With the identification of the gene, it is now possible to protect axons as well as neuronal cell bodies.


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