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The Journal of Neuroscience, January 21, 2009, 29(3):653-668; doi:10.1523/JNEUROSCI.3814-08.2009

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Cellular/Molecular
Non-Nuclear Wld^S Determines Its Neuroprotective Efficacy for Axons and Synapses In Vivo

Bogdan Beirowski,¹ Elisabetta Babetto,¹ Jon Gilley,¹ Francesca Mazzola,² Laura Conforti,¹ Lucie Janeckova,¹ Giulio Magni,² Richard R. Ribchester,³ and Michael P. Coleman¹

¹Laboratory of Molecular Signalling, The Babraham Institute, Cambridge CB22 3AT, United Kingdom, ²Institute of Biochemical Biotechnologies, University of Ancona, Via Ranieri, 60131 Ancona, Italy, and ³Centre for Neuroscience Research, University of Edinburgh, Edinburgh EH8 9JZ, United Kingdom

Correspondence should be addressed to Dr. Michael P. Coleman, Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK. Email: michael.coleman{at}bbsrc.ac.uk

Axon degeneration contributes widely to neurodegenerative disease but its regulation is poorly understood. The Wallerian degeneration slow (Wld^S) protein protects axons dose-dependently in many circumstances but is paradoxically abundant in nuclei. To test the hypothesis that Wld^S acts within nuclei in vivo, we redistributed it from nucleus to cytoplasm in transgenic mice. Surprisingly, instead of weakening the phenotype as expected, extranuclear Wld^S significantly enhanced structural and functional preservation of transected distal axons and their synapses. In contrast to native Wld^S mutants, distal axon stumps remained continuous and ultrastructurally intact up to 7 weeks after injury and motor nerve terminals were robustly preserved even in older mice, remaining functional for 6 d. Moreover, we detect extranuclear Wld^S for the first time in vivo, and higher axoplasmic levels in transgenic mice with Wld^S redistribution. Cytoplasmic Wld^S fractionated predominantly with mitochondria and microsomes. We conclude that Wld^S can act in one or more non-nuclear compartments to protect axons and synapses, and that molecular changes can enhance its therapeutic potential.

Key words: axon degeneration; Wallerian degeneration; neurodegeneration; slow Wallerian degeneration gene; neuroprotection; neuromuscular junction

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Received Aug. 11, 2008; revised Nov. 8, 2008; accepted Dec. 4, 2008.

Correspondence should be addressed to Dr. Michael P. Coleman, Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB22 3AT, UK. Email: michael.coleman{at}bbsrc.ac.uk

This article has been cited by other articles:

				Y. Sasaki, B. P. S. Vohra, R. H. Baloh, and J. Milbrandt Transgenic Mice Expressing the Nmnat1 Protein Manifest Robust Delay in Axonal Degeneration In Vivo J. Neurosci., May 20, 2009; 29(20): 6526 - 6534. [Abstract] [Full Text] [PDF]

				L. Conforti, A. Wilbrey, G. Morreale, L. Janeckova, B. Beirowski, R. Adalbert, F. Mazzola, M. Di Stefano, R. Hartley, E. Babetto, et al. WldS protein requires Nmnat activity and a short N-terminal sequence to protect axons in mice J. Cell Biol., February 23, 2009; 184(4): 491 - 500. [Abstract] [Full Text] [PDF]

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