NAD+ acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration
NAD+ acts on mitochondrial SirT3 to prevent axonal caspase activation and axonal degeneration
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DOI：
10.1096/fj.13-229781
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发表时间：
2013-12-01
期刊：
影响因子：
4.8
通讯作者：
Peyrin, Jean-Michel
中科院分区：
文献类型：
--
作者：
Magnifico, Sebastien;Saias, Laure;Peyrin, Jean-Michel
在慢性退行性综合征中，神经元死亡发生在很长一段时间内，在此期间细胞逐渐失去轴突，并最终失去细胞体。虽然细胞凋亡被认为是神经元死亡的关键事件，但涉及中枢神经系统轴突退化的分子机制尚不清楚。由于中枢神经系统神经元的高度极化表型，不同的神经元亚室可能成为轻度重复和局部攻击的目标。这种局部启动的有害信号转导途径理论上可以通过细胞质传播。然而，轴突退行性信号在哪里开始，这些早期信号是什么，以及它们如何导致轴突变性是没有答案的问题，这些问题限制了我们对神经退行性疾病的理解和我们识别新治疗靶点的能力。利用一种适用于中枢神经系统原代神经元的微流体培养装置，允许特异性进入轴突和体突室，我们分析了分化神经元轴突变性的分子通路。我们在这里表明，局部应用促凋亡刺激体树突状室触发涉及半胱天冬酶依赖性轴突变性的死亡模式。利用互补的药理学和遗传学方法，我们进一步证明了NAD（+）和葡萄酒多酚可以防止轴突凋亡，并通过轴突线粒体SirT3激活起作用。
In chronic degenerative syndromes, neuronal death occurs over long periods, during which cells progressively lose their axons and, ultimately, their cell bodies. Although apoptosis is recognized as a key event in neuronal death, the molecular mechanisms involved in CNS axons degeneration are poorly understood. Due to the highly polarized phenotypes of CNS neurons, the different neuronal subcompartments are likely to be targeted by light repetitive and localized aggression. Such locally initiated deleterious signal transduction pathways could theoretically spread through the cytoplasm. However, where axon-degenerative signals initiate, what these early signals are, and how they lead to axon degeneration are unanswered questions that limit our understanding of neurodegenerative diseases and our ability to identify novel therapeutic targets. Using a microfluidic culture device adapted to CNS primary neurons, allowing specific access to the axonal and somatodendritic compartments, we analyzed the molecular pathways involved in axonal degeneration of differentiated neurons. We show here that local application of proapoptotic stimuli on the somatodentritic compartment triggers a dying-back pattern involving caspase-dependent axonal degeneration. Using complementary pharmacological and genetic approaches, we further demonstrate that NAD(+) and grape wine polyphenols prevent axonal apoptosis and act via mitochondrial SirT3 activation in axons.