Prolyl hydroxylase regulates axonal rewiring and motor recovery after traumatic brain injury.
Prolyl hydroxylase regulates axonal rewiring and motor recovery after traumatic brain injury.
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DOI：
10.1038/cddis.2015.5
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发表时间：
2015-02-12
影响因子：
9
通讯作者：
Yamashita T
中科院分区：
文献类型：
--
作者：
Miyake S;Muramatsu R;Hamaguchi M;Yamashita T
Prolyl 4-羟化酶（PHD1， PHD2和PHD3）是细胞氧传感器的一个组成部分，通过缺氧/应激调节基因转录稳定氧浓度来调节适应性反应。在常压条件下，需要PHD2来稳定缺氧诱导因子。PHD2的沉默导致细胞内信号的激活，包括RhoA和RhoA相关蛋白激酶（ROCK），它们是神经突起生长的关键调节因子。在这项研究中，我们确定在培养的皮质神经元中，PHD2的遗传或药理学抑制通过rock依赖机制阻止了神经突的伸长。然后，我们探讨了博士在成年小鼠创伤性脑损伤后轴突重组中的作用。运动皮质的单侧破坏会导致作为下行运动通路一部分的皮质脊髓束（CST）的破坏而导致行为缺陷。在脊髓中，纤维从CST的完整侧萌发到失神经侧被认为有助于损伤后的恢复过程。将PHD抑制剂注入运动皮质完整侧，会破坏CST侧支的自发形成和感觉运动皮质损伤后的功能恢复。这些发现表明博士在损伤后代偿轴突网络的形成中起重要作用，并可能代表中枢神经系统疾病的新分子靶点。
Prolyl 4-hydroxylases (PHDs; PHD1, PHD2, and PHD3) are a component of cellular oxygen sensors that regulate the adaptive response depending on the oxygen concentration stabilized by hypoxia/stress-regulated genes transcription. In normoxic condition, PHD2 is required to stabilize hypoxia inducible factors. Silencing of PHD2 leads to the activation of intracellular signaling including RhoA and Rho-associated protein kinase (ROCK), which are key regulators of neurite growth. In this study, we determined that genetic or pharmacological inhibition of PHD2 in cultured cortical neurons prevents neurite elongation through a ROCK-dependent mechanism. We then explored the role of PHDs in axonal reorganization following a traumatic brain injury in adult mice. Unilateral destruction of motor cortex resulted in behavioral deficits due to disruption of the corticospinal tract (CST), a part of the descending motor pathway. In the spinal cord, sprouting of fibers from the intact side of the CST into the denervated side is thought to contribute to the recovery process following an injury. Intracortical infusion of PHD inhibitors into the intact side of the motor cortex abrogated spontaneous formation of CST collaterals and functional recovery after damage to the sensorimotor cortex. These findings suggest PHDs have an important role in the formation of compensatory axonal networks following an injury and may represent a new molecular target for the central nervous system disorders.