Wld(S )but not Nmnat1 protects dopaminergic neurites from MPP(+ )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.