Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies (Publication with Expression of Concern. See vol. 126, pg. 2773, 2016) (Retracted article. See vol. 127, pg. 1115, 2017)
Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies (Publication with Expression of Concern. See vol. 126, pg. 2773, 2016) (Retracted article. See vol. 127, pg. 1115, 2017)
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DOI：
10.1172/jci84505
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发表时间：
2016-03-01
影响因子：
15.9
通讯作者：
Tricaud, Nicolas
中科院分区：
文献类型：
--
作者：
Gonzalez, Sergio;Berthelot, Jade;Tricaud, Nicolas
雪旺细胞在周围神经轴突周围产生髓鞘。髓鞘形成对于动作电位的快速传播至关重要，大量获得性和遗传性周围神经病（例如糖尿病神经病或腓骨肌萎缩症）就说明了这一点，这些病通常与脱髓鞘过程相关。然而，在这些疾病中触发脱髓鞘程序的早期分子事件仍然未知。在这里，我们在脱髓鞘小鼠模型中使用病毒传递的荧光探针和体内延时成像来研究脱髓鞘过程的潜在机制。我们证明了线粒体！坐骨神经损伤后电压依赖性阴离子通道 1 (VDAC1) 释放的钙通过 ERK1/2、p38、JNK 和 c-JUN 激活触发雪旺细胞脱髓鞘。在糖尿病小鼠中，VDAC1 活性发生改变，产生了线粒体！雪旺细胞细胞质中的钙泄漏，从而引发细胞脱髓鞘。而且，线粒体减少了！通过 shRNA 介导的 VDAC1 沉默或药物抑制，钙释放可防止脱髓鞘，导致糖尿病神经病变和腓骨肌萎缩症啮齿动物模型的神经传导和神经肌肉性能恢复。因此，本研究将线粒体确定为周围脱髓鞘分子机制的早期关键因素，并为治疗脱髓鞘周围神经病开辟了潜在的机会。
Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth diseases, that are commonly associated with a process of demyelination. However, the early molecular events that trigger the demyelination program in these diseases remain unknown. Here, we used virally delivered fluorescent probes and in vivo time-lapse imaging in a mouse model of demyelination to investigate the underlying mechanisms of the demyelination process. We demonstrated that mitochondria! calcium released by voltage-dependent anion channel 1 (VDAC1) after sciatic nerve injury triggers Schwann cell demyelination via ERK1/2, p38, JNK, and c-JUN activation. In diabetic mice, VDAC1 activity was altered, resulting in a mitochondria! calcium leak in Schwann cell cytoplasm, thereby priming the cell for demyelination. Moreover, reduction of mitochondria! calcium release, either by shRNA-mediated VDAC1 silencing or pharmacological inhibition, prevented demyelination, leading to nerve conduction and neuromuscular performance recovery in rodent models of diabetic neuropathy and Charcot-Marie-Tooth diseases. Therefore, this study identifies mitochondria as the early key factor in the molecular mechanism of peripheral demyelination and opens a potential opportunity for the treatment of demyelinating peripheral neuropathies.