Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.
Mitochondria and Caspases Tune Nmnat-Mediated Stabilization to Promote Axon Regeneration.
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DOI：
10.1371/journal.pgen.1006503
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发表时间：
2016-12
期刊：
影响因子：
4.5
通讯作者：
Rolls MM
中科院分区：
文献类型：
--
作者：
Chen L;Nye DM;Stone MC;Weiner AT;Gheres KW;Xiong X;Collins CA;Rolls MM
轴突损伤可导致多种细胞生存反应，包括稳定性增加和轴突再生。使用可访问的果蝇模型系统，我们研究了损伤反应的调节及其关系。轴突损伤可以稳定细胞的其余部分，包括整个树突轴。轴突损伤后，我们发现树突中的线粒体裂变上调，并且减少裂变增加了稳定性或神经保护（NP）。因此，轴突损伤似乎既会开启 NP，又会通过激活线粒体裂变来抑制它。我们还发现 caspase 是轴突损伤介导的 NP 的负调节因子，因此线粒体裂变可以通过 caspase 激活来控制 NP。除了 NP 的负调节因子外，我们发现烟酰胺单核苷酸腺苷酸转移酶 (Nmnat) 对于此类 NP 绝对是必需的。以前与 NP 相关的微管动力学增加需要 Nmnat。事实上，在没有轴突损伤的情况下，Nmnat 过度表达足以诱导 NP 并增加微管动力学。 NP 还需要 DLK、JNK 和 fos。由于 NP 发生在轴突再生之前，并且 NP 似乎被主动下调，因此我们测试了过量的 NP 是否会抑制再生。事实上，Nmnat 过度表达和 caspase 减少都会减少再生。此外，fos 或 JNK 的过度表达以 Nmnat 依赖性方式延长了 NP 的时程并抑制了再生。这些数据表明，NP 和再生是对轴突损伤的相互冲突的反应，并且促进 NP 的治疗策略可能会减少再生。与许多其他细胞类型不同，大多数神经元会持续一生。当受伤时，这些细胞通常会激活生存和修复策略，而不是死亡。其中一种反应是轴突受伤后的再生。轴突再生是一个保守的过程，由蠕虫、苍蝇和哺乳动物中相同的信号级联激活。令人惊讶的是，我们发现这种信号级联首先启动不同的响应。第一个反应使细胞稳定，线粒体裂变和半胱天冬酶对其进行下调，从而在以后实现最大程度的再生。我们提出，神经元以多步骤过程对轴突损伤做出反应，其中包括细胞稳定的早期锁定阶段，然后是再生最大化的更具可塑性的状态。
Axon injury can lead to several cell survival responses including increased stability and axon regeneration. Using an accessible Drosophila model system, we investigated the regulation of injury responses and their relationship. Axon injury stabilizes the rest of the cell, including the entire dendrite arbor. After axon injury we found mitochondrial fission in dendrites was upregulated, and that reducing fission increased stabilization or neuroprotection (NP). Thus axon injury seems to both turn on NP, but also dampen it by activating mitochondrial fission. We also identified caspases as negative regulators of axon injury-mediated NP, so mitochondrial fission could control NP through caspase activation. In addition to negative regulators of NP, we found that nicotinamide mononucleotide adenylyltransferase (Nmnat) is absolutely required for this type of NP. Increased microtubule dynamics, which has previously been associated with NP, required Nmnat. Indeed Nmnat overexpression was sufficient to induce NP and increase microtubule dynamics in the absence of axon injury. DLK, JNK and fos were also required for NP. Because NP occurs before axon regeneration, and NP seems to be actively downregulated, we tested whether excessive NP might inhibit regeneration. Indeed both Nmnat overexpression and caspase reduction reduced regeneration. In addition, overexpression of fos or JNK extended the timecourse of NP and dampened regeneration in a Nmnat-dependent manner. These data suggest that NP and regeneration are conflicting responses to axon injury, and that therapeutic strategies that boost NP may reduce regeneration. Unlike many other cell types, most neurons last a lifetime. When injured, these cells often activate survival and repair strategies rather than dying. One such response is regeneration of the axon after it is injured. Axon regeneration is a conserved process activated by the same signaling cascade in worms, flies and mammals. Surprisingly we find that this signaling cascade first initiates a different response. This first response stabilizes the cell, and its downregulation by mitochondrial fission and caspases allows for maximum regeneration at later times. We propose that neurons respond to axon injury in a multi-step process with an early lock-down phase in which the cell is stabilized, followed by a more plastic state in which regeneration is maximized.
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影响因子：
11.8
作者：
Goyal, Gaurav;Fell, Brennan;Sarin, Apurva;Youle, Richard J.;Sriram, V.
通讯作者：
Sriram, V.
DOI：
10.1083/jcb.200601067
发表时间：
2006-05-22
期刊：
The Journal of cell biology
影响因子：
--
作者：
Glater EE;Megeath LJ;Stowers RS;Schwarz TL
通讯作者：
Schwarz TL
DOI：
10.1523/jneurosci.4065-10.2011
发表时间：
2011-01-19
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Barrientos SA;Martinez NW;Yoo S;Jara JS;Zamorano S;Hetz C;Twiss JL;Alvarez J;Court FA
通讯作者：
Court FA
影响因子：
9.2
作者：
Avery, Michelle A;Rooney, Timothy M;Pandya, Jignesh D;Wishart, Thomas M;Gillingwater, Thomas H;Geddes, James W;Sullivan, Patrick G;Freeman, Marc R
通讯作者：
Freeman, Marc R
影响因子：
9.2
作者：
Fang, Yanshan;Soares, Lorena;Teng, Xiuyin;Geary, Melissa;Bonini, Nancy M
通讯作者：
Bonini, Nancy M