Axonal degeneration is mediated by the mitochondrial permeability transition pore.
Axonal degeneration is mediated by the mitochondrial permeability transition pore.
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DOI：
10.1523/jneurosci.4065-10.2011
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发表时间：
2011-01-19
期刊：
影响因子：
--
通讯作者：
Court FA
中科院分区：
文献类型：
--
作者：
Barrientos SA;Martinez NW;Yoo S;Jara JS;Zamorano S;Hetz C;Twiss JL;Alvarez J;Court FA
轴突变性是一种活跃的过程，与机械性、代谢性、感染性、毒性、遗传性和炎症性刺激引发的神经退行性疾病有关。这种退化过程会导致永久性的功能丧失，因此它代表了神经保护策略的焦点。一些信号通路与轴突变性有关，但这种自我毁灭过程的综合机制的鉴定仍然难以捉摸。在这里，我们表明，由不同的机械和毒性损伤引发的快速轴突变性依赖于线粒体通透性过渡孔（mPTP）的激活。在离体和离体小鼠和大鼠模型系统中，mPTP的功能成分亲环蛋白D的药理学和遗传学靶向，保护被切断的轴突和长春新碱处理的神经元免受轴突变性。这些影响在周围和中枢神经系统的轴突中都观察到。我们的研究结果表明，mPTP是轴突变性的关键效应因子，在轴突变性上，几个独立的信号通路汇合。由于轴突和突触变性越来越多地被认为是神经退行性疾病的早期病理事件，我们的工作确定了在导致轴突丧失和随后的功能损伤的各种情况下进行治疗干预的潜在目标。
Axonal degeneration is an active process that has been associated with neurodegenerative conditions triggered by mechanical, metabolic, infectious, toxic, hereditary and inflammatory stimuli. This degenerative process can cause permanent loss of function, so it represents a focus for neuroprotective strategies. Several signaling pathways are implicated in axonal degeneration, but identification of an integrative mechanism for this self-destructive process has remained elusive. Here, we show that rapid axonal degeneration triggered by distinct mechanical and toxic insults is dependent on the activation of the mitochondrial permeability transition pore (mPTP). Both pharmacological and genetic targeting of cyclophilin D, a functional component of the mPTP, protects severed axons and vincristine-treated neurons from axonal degeneration in ex vivo and in vitro mouse and rat model systems. These effects were observed in axons from both the peripheral and central nervous system. Our results suggest that the mPTP is a key effector of axonal degeneration, upon which several independent signaling pathways converge. Since axonal and synapse degeneration are increasingly considered early pathological events in neurodegeneration, our work identifies a potential target for therapeutic intervention in a wide variety of conditions that lead to loss of axons and subsequent functional impairment.