WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity.
WldS but not Nmnat1 protects dopaminergic neurites from MPP+ neurotoxicity.
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DOI：
10.1186/1750-1326-7-5
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发表时间：
2012-02-08
影响因子：
15.1
通讯作者：
O'Malley KL
中科院分区：
文献类型：
--
作者：
Antenor-Dorsey JA;O'Malley KL
WldS小鼠突变体(“沃勒变性-慢”)在包括帕金森氏病体内模型在内的各种疾病中延缓轴突退化。WldS介导的轴突保护机制尚不清楚，尽管许多研究将WldS的神经保护归因于融合蛋白的NAD+合成Nmnat1部分。在这里，我们使用分离的多巴胺能培养来检验催化活性Nmnat1保护多巴胺能神经元免受毒素介导的轴突损伤的假设。利用突变小鼠和多巴胺能神经元的慢病毒转导，目前的发现表明，WldS而不是Nmnat1、Nmnat3或细胞质靶向的Nmnat1保护多巴胺轴突免受帕金森病类似物N-甲基-4-苯基吡啶(MPP+)的影响。此外，NAD+的合成不是必需的，因为酶失活的WldS仍然具有保护作用。此外，NAD+本身具有轴性保护作用，与WldS一起在MPP+模型中是相加的。我们的数据表明，NAD+和WldS通过单独的、可能是平行的机制来保护多巴胺轴突。由于MPP+被认为损害了线粒体的功能，这些结果表明WldS可能参与了维持线粒体健康或维持细胞代谢。
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. 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. 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.
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影响因子：
15.1
作者：
Bernstein AI;Garrison SP;Zambetti GP;O'Malley KL
通讯作者：
O'Malley KL
影响因子：
9.2
作者：
Ferri, A;Sanes, JR;Kato, AC
通讯作者：
Kato, AC
影响因子：
5.3
作者：
Hasbani, Daphne M.;O'Malley, Karen L.
通讯作者：
O'Malley, Karen L.
影响因子：
5.3
作者：
Babetto, Elisabetta;Beirowski, Bogdan;Coleman, Michael P.
通讯作者：
Coleman, Michael P.
DOI：
10.1073/pnas.95.17.9985
发表时间：
1998-08-18
影响因子：
11.1
作者：
Coleman, MP;Conforti, L;Perry, VH
通讯作者：
Perry, VH