DUSP4 appears to be a highly localized endogenous inhibitor of epileptic signaling in human neocortex.
DUSP4 appears to be a highly localized endogenous inhibitor of epileptic signaling in human neocortex.
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DOI：
10.1016/j.nbd.2020.105073
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发表时间：
2020-11
影响因子：
6.1
通讯作者：
Loeb JA
中科院分区：
文献类型：
--
作者：
Kirchner A;Bagla S;Dachet F;Loeb JA
我们之前发现丝裂原激活蛋白激酶 (MAPK) 通路在癫痫活动高的大脑区域局部上调，并表明抑制 MAPK 信号传导可减少动物模型中的癫痫发作。在这里，我们研究了 MAPK 通路的激活剂和抑制剂如何在人类癫痫皮层中表达，以及它们如何有助于癫痫信号传导的定位。我们根据 20 名患者的长期颅内记录的癫痫活动，定位了人类癫痫新皮质组织中的基因和蛋白质表达。通过人 Sh-SY5Y 细胞系去极化进行的后续机制研究用于模拟人脑中的癫痫活动。差异表达基因的聚类算法识别出与其他 MAPK 基因不同的独特基因表达簇。该簇内有双特异性磷酸酶 4 (DUSP4)，一种有效的 MAPK 抑制剂。原位杂交研究揭示了 2/3 层大脑区域中 DUSP4 mRNA 的局灶性斑块与 MAPK 信号基因的急剧减少相关。体外去极化导致 DUSP4 蛋白快速且短暂的诱导，进而降低 MAPK 活性。 DUSP4 蛋白的活性依赖性诱导是短暂的并且需要 MAPK 信号传导。癫痫活动较低的人类癫痫大脑区域具有较低的 MAPK 活性和较高的 DUSP4 蛋白水平。 DUSP4 是人癫痫大脑中促癫痫 MAPK 信号传导的高度局部化、内源性反馈抑制剂。因此，增加 DUSP4 表达可能是预防癫痫回路发展和扩散的一种新的治疗方法。
We previously identified the Mitogen Activated Protein Kinase (MAPK) pathway as focally upregulated in brain regions with high epileptic activity and showed that inhibition of MAPK signaling reduces epileptic spiking in an animal model. Here we examined how activators and inhibitors of the MAPK pathway are expressed in human epileptic cortex and how these could contribute to the localization of epileptic signaling. We localized gene and protein expression in human epileptic neocortical tissues based on epileptic activities from 20 patients based on long-term intracranial recordings. Follow-up mechanistic studies by depolarization of human Sh-SY5Y cell line were used to model epileptic activity in the human brain. A clustering algorithm of differentially expressed genes identified a unique gene expression cluster distinct from other MAPK genes. Within this cluster was dual specificity phosphatase 4 (DUSP4), a potent MAPK inhibitor. In situ hybridization studies revealed focal patches of DUSP4 mRNA in layer 2/3 brain regions associated with a dramatic reduction in MAPK signaling genes. In vitro depolarization led to the rapid and transient induction of DUSP4 protein, which, in turn, reduced MAPK activity. Activity-dependent induction of DUSP4 protein was transient and required MAPK signaling. Human epileptic brain regions with lower epileptic activity had lower MAPK activity and higher DUSP4 protein levels. DUSP4 is a highly localized, endogenous feedback inhibitor of pro-epileptogenic MAPK signaling in the human epileptic brain. Increasing DUSP4 expression could therefore be a novel therapeutic approach to prevent the development and spread of epileptic circuits.
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影响因子：
6.1
作者：
Barkmeier DT;Senador D;Leclercq K;Pai D;Hua J;Boutros NN;Kaminski RM;Loeb JA
通讯作者：
Loeb JA
影响因子：
14.5
作者：
Dachet, Fabien;Bagla, Shruti;Loeb, Jeffrey A.
通讯作者：
Loeb, Jeffrey A.
影响因子：
5.6
作者：
HAUSER, WA;ANNEGERS, JF;KURLAND, LT
通讯作者：
KURLAND, LT
影响因子：
4.8
作者：
Crowell, Sara;Wancket, Lyn M.;Liu, Yusen
通讯作者：
Liu, Yusen
影响因子：
4.8
作者：
MISRAPRESS, A;RIM, CS;STORK, PJS
通讯作者：
STORK, PJS