WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity
The WldS mouse mutant ("Wallerian degeneration-slow") delays axonal degeneration in a variety of disorders including in vivo models of Parkinson's disease. The mechanisms underlying WldS -mediated axonal protection are unclear, although many studies have attributed WldS 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 WldS 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 WldS still protects.
In addition, NAD+ by itself is axonally protective and together with WldS is additive in the MPP+ model.
Conclusions:
Our data suggest that NAD+ and WldS act through separate and possibly parallel mechanisms to protect dopamine axons. As MPP+ is thought to impair mitochondrial function, these results suggest that WldS might be involved in preserving mitochondrial health or maintaining cellular metabolism.
Author: Jo Ann V Antenor-DorseyKaren L O'Malley
Credits/Source: Molecular Neurodegeneration 2012, 7:5
Published on: 2012-02-08
Copyright by the authors listed above - made available via BioMedCentral (Open Access). Please
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