WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity

Molecular Neurodegeneration

Karen L O'Malley¹  Jo Ann V Antenor-Dorsey¹ 

[1] Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, MO, 63110, USA

关键词: axonal degeneration;    dopaminergic neurons;    MPP⁺;    Parkinson's disease;    Nmnat1;    Wld^S;   

Others  :  863940
DOI  :  10.1186/1750-1326-7-5

 received in 2011-08-10, accepted in 2012-02-08,  发布年份 2012

【 摘 要 】

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.

【 授权许可】

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

【 图 表 】

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