Non-nuclear Wld^S determines its neuroprotective efficacy for axons and synapses in vivo

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 nonnuclear compartments to protect axons and synapses, and that molecular changes can enhance its therapeutic potential.