TY - JOUR
T1 - Wld S but not Nmnat1 protects dopaminergic neurites from MPP + neurotoxicity
AU - Antenor-Dorsey, Jo Ann V.
AU - O'Malley, Karen L.
N1 - Funding Information:
This work was supported by National Institutes of Health Grants NS39084 (K. L.O.) and National Institutes of Health Neuroscience Blueprint Core Grant NS057105 to Washington University. This work was also supported by the Bakewell Family Foundation. We thank Steven K. Harmon for technical support and Drs. Michael Coleman, Jeffrey Milbrandt, Christian Sheline, Valeria Cavalli and Jeong Sook Kim-Han for materials and helpful discussions.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - MPP
KW - Nmnat1
KW - Parkinson's disease
KW - Wld
KW - axonal degeneration
KW - dopaminergic neurons
UR - http://www.scopus.com/inward/record.url?scp=84856608720&partnerID=8YFLogxK
U2 - 10.1186/1750-1326-7-5
DO - 10.1186/1750-1326-7-5
M3 - Article
C2 - 22315973
AN - SCOPUS:84856608720
SN - 1750-1326
VL - 7
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 5
ER -