Carvajal Francisco J, Cerpa Waldo
Laboratorio de Función y Patología Neuronal, Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas 6200000, Chile.
Antioxidants (Basel). 2021 Oct 5;10(10):1575. doi: 10.3390/antiox10101575.
Traumatic Brain Injury (TBI) mediates neuronal death through several events involving many molecular pathways, including the glutamate-mediated excitotoxicity for excessive stimulation of N-methyl-D-aspartate receptors (NMDARs), producing activation of death signaling pathways. However, the contribution of NMDARs (distribution and signaling-associated to the distribution) remains incompletely understood. We propose a critical role of STEP (Striatal-Enriched protein tyrosine phosphatase) in TBI; this phosphatase regulates the dephosphorylated state of the GluN2B subunit through two pathways: by direct dephosphorylation of tyrosine-1472 and indirectly via dephosphorylation and inactivation of Fyn kinase. We previously demonstrated oxidative stress's contribution to NMDAR signaling and distribution using SOD2 mice such a model. We performed TBI protocol using a controlled frontal impact device using C57BL/6 mice and SOD2 animals. After TBI, we found alterations in cognitive performance, NMDAR-dependent synaptic function (decreased synaptic form of NMDARs and decreased synaptic current NMDAR-dependent), and increased STEP activity. These changes are reduced partially with the STEP-inhibitor TC-2153 treatment in mice subjected to TBI protocol. This study contributes with evidence about the role of STEP in the neuropathological progression after TBI and also the alteration in their activity, such as an early biomarker of synaptic damage in traumatic lesions.
创伤性脑损伤（TBI）通过涉及许多分子途径的多个事件介导神经元死亡，包括谷氨酸介导的兴奋性毒性，即过度刺激N-甲基-D-天冬氨酸受体（NMDARs），从而激活死亡信号通路。然而，NMDARs（分布以及与分布相关的信号传导）的作用仍未完全了解。我们提出富含纹状体蛋白酪氨酸磷酸酶（STEP）在TBI中起关键作用；这种磷酸酶通过两条途径调节GluN2B亚基的去磷酸化状态：通过直接使酪氨酸-1472去磷酸化以及间接通过使Fyn激酶去磷酸化并使其失活。我们之前使用SOD2小鼠等模型证明了氧化应激对NMDAR信号传导和分布的作用。我们使用可控额叶撞击装置对C57BL/6小鼠和SOD2动物进行了TBI实验方案。TBI后，我们发现认知功能、NMDAR依赖的突触功能（NMDARs的突触形式减少以及NMDAR依赖的突触电流减少）发生改变，并且STEP活性增加。在接受TBI实验方案的小鼠中，用STEP抑制剂TC-2153治疗可部分减轻这些变化。本研究为STEP在TBI后神经病理进展中的作用以及其活性改变提供了证据，例如其活性改变可作为创伤性损伤中突触损伤的早期生物标志物。
