Wld S but not Nmnat1 protects dopaminergic neurites from MPP + neurotoxicity

Abstract

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. © 2012 Antenor-Dorsey and O'Malley; licensee BioMed Central Ltd.