| Summary: | <p>Abstract</p> <p>Background</p> <p>The <it>Wld<sup>S </sup></it>mouse mutant ("Wallerian degeneration-slow") delays axonal degeneration in a variety of disorders including <it>in vivo </it>models of Parkinson's disease. The mechanisms underlying <it>Wld<sup>S </sup></it>-mediated axonal protection are unclear, although many studies have attributed <it>Wld<sup>S </sup></it>neuroprotection to the NAD<sup>+</sup>-synthesizing Nmnat1 portion of the fusion protein. Here, we used dissociated dopaminergic cultures to test the hypothesis that catalytically active Nmnat1 protects dopaminergic neurons from toxin-mediated axonal injury.</p> <p>Results</p> <p>Using mutant mice and lentiviral transduction of dopaminergic neurons, the present findings demonstrate that <it>Wld<sup>S </sup></it>but not Nmnat1, Nmnat3, or cytoplasmically-targeted Nmnat1 protects dopamine axons from the parkinsonian mimetic N-methyl-4-phenylpyridinium (MPP<sup>+</sup>). Moreover, NAD<sup>+ </sup>synthesis is not required since enzymatically-inactive <it>Wld<sup>S </sup></it>still protects. In addition, NAD<sup>+ </sup>by itself is axonally protective and together with <it>Wld<sup>S </sup></it>is additive in the MPP<sup>+ </sup>model.</p> <p>Conclusions</p> <p>Our data suggest that NAD<sup>+ </sup>and <it>Wld<sup>S </sup></it>act through separate and possibly parallel mechanisms to protect dopamine axons. As MPP<sup>+ </sup>is thought to impair mitochondrial function, these results suggest that <it>Wld<sup>S </sup></it>might be involved in preserving mitochondrial health or maintaining cellular metabolism.</p>
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