Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress
Nmnat delays axonal degeneration caused by mitochondrial and oxidative stress
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DOI：
10.1523/jneurosci.0525-08.2008
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发表时间：
2008-05-07
影响因子：
5.3
通讯作者：
Milbrandt, Jeffrey
中科院分区：
文献类型：
--
作者：
Press, Craig;Milbrandt, Jeffrey
轴突变性是与线粒体功能障碍相关的许多神经系统疾病的显著特征，包括帕金森病、运动神经元病和遗传性周围神经病。对Wld（s）突变小鼠的研究表明，轴突变性是一个活跃的过程，该小鼠响应于轴突损伤而经历延迟的沃勒变性。在许多神经退行性疾病模型中，Wlds小鼠的轴突变性和疾病进展也较慢。Wlds突变导致嵌合蛋白的产生，所述嵌合蛋白含有烟酰胺单核苷酸腺苷酰转移酶1（Nmnat 1）的全长编码序列，其单独足以在体外保护轴突。为了测试Nmnat表达增加对线粒体功能障碍诱导的轴突变性的影响，我们检查了用鱼藤酮处理的背根神经节（DRG）神经元。鱼藤酮诱导DRG神经元发生深刻的轴突变性;然而，Nmnat的表达延迟了这种变性。Nmnat介导的保护导致轴突积累和对活性氧（ROS）的敏感性降低，但不影响鱼藤酮诱导的神经元ATP损失率的变化。Nmnat还预防了暴露于外源性氧化剂引起的轴突变性，并降低了长春新碱治疗后轴突ROS的水平，进一步支持了Nmnat通过减轻ROS的作用促进轴突保护的观点。
Axonal degeneration is a prominent feature of many neurological disorders that are associated with mitochondrial dysfunction, including Parkinson's disease, motor neuron disease, and inherited peripheral neuropathies. Studies of the Wld(s) mutant mouse, which undergoes delayed Wallerian degeneration in response to axonal injury, suggest that axonal degeneration is an active process. Wlds mice also have slower axonal degeneration and disease progression in numerous models of neurodegenerative disease. The Wlds mutation results in the production of a chimeric protein that contains the full-length coding sequence of nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1), which alone is sufficient for axonal protection in vitro. To test the effects of increased Nmnat expression on axonal degeneration induced by mitochondrial dysfunction, we examined dorsal root ganglion (DRG) neurons treated with rotenone. Rotenone induced profound axonal degeneration in DRG neurons; however, this degeneration was delayed by expression of Nmnat. Nmnat-mediated protection resulted in decreased axonal accumulation and sensitivity to reactive oxygen species (ROS) but did not affect the change in the rate of rotenone-induced loss in neuronal ATP. Nmnat also prevented axonal degeneration caused by exposure to exogenous oxidants and reduced the level of axonal ROS after treatment with vincristine, further supporting the idea that Nmnat promotes axonal protection by mitigating the effects of ROS.