WldS but not Nmnat1 protects dopaminergic neurites from MPP plus neurotoxicity

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