WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity.
BACKGROUND
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.
Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, MO 63110, USA.
Jo Ann V
JA
Antenor-Dorsey
Karen L
KL
O'Malley
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000648:ultrastructure; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009243:NAD / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism / Q000502:physiology*; D010300:Parkinson Disease / Q000235:genetics; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism
D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C442580:Wld protein, mouse; D009243:NAD; D009612:Nicotinamide-Nucleotide Adenylyltransferase; C510972:Nmnat1 protein, mouse; D015655:1-Methyl-4-phenylpyridinium