Non-nuclear WldS determines its neuroprotective efficacy for axons and synapses in vivo

Abstract

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 WldS acts within nuclei in vivo, we redistributed it from nucleus to cytoplasm in transgenic mice. Surprisingly, instead of weakening the phenotype as expected, extranuclear WldS significantly enhanced structural and functional preservation of transected distal axons and their synapses. In contrast to native WldS 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 WldS for the first time in vivo, and higher axoplasmic levels in transgenic mice with WldS redistribution. Cytoplasmic WldS fractionated predominantly with mitochondria and microsomes. We conclude that WldS can act in one or more nonnuclear compartments to protect axons and synapses, and that molecular changes can enhance its therapeutic potential. Copyright © 2009 Society for Neuroscience.