INSERM Unité 901, Marseille, France.
Curr Pharm Des. 2011;17(19):1914-23. doi: 10.2174/138161211796718198.
As a key component of the plasminogen activation system, uPAR, the receptor for the plasminogen activator of the urokinase type, is involved in many physiological and pathological processes. Besides its classical roles, there has been increased evidence that uPAR or uPAR-associated pathways, participate in the development, in the functioning and in the pathology of the central nervous system. Qualitative and quantitative changes in the expressions of uPAR and of its canonical ligand uPA have been observed in a large variety of epileptic disorders, either in human or in animal models, as well as in other brain diseases (stroke and brain trauma, multiple sclerosis, Alzheimer's disease, cerebral malaria, HIV-associated leukoencephalopathy and encephalitis). The variety of such pathological conditions and the different brain areas and cell types involved, likely reflects the wide range and the complexity of the multiple and somehow intertwined pathophysiological mechanisms related with uPAR. In the mouse, the knock-out of the Upar-encoding gene (Plaur) leads to significant and nearly complete loss in parvalbumin-containing interneurons during brain development. This is associated with increased susceptibility to spontaneous and chemically-induced seizures and with increased anxiety and impaired social interactions. The recent identification of the novel uPAR ligand SRPX2 (Sushi repeat protein, X-linked 2) and the regulation of both the SRPX2 and PLAUR genes by transcription factor FOXP2 has shed novel and exciting insights into the role of uPAR-related molecular networks in rolandic epilepsy, in developmental verbal dyspraxia, in perisylvian polymicrogyria, and generally in disorders of the speech areas and circuits. uPAR, its regulators and partners, as well as other proteins containing Ly-6/uPAR/alpha-neurotoxin domains, represent key entry points for present and future studies not only on speech-related disorders but also on epilepsy and autism spectrum disorders.
作为纤溶酶原激活系统的关键组成部分，尿激酶型纤溶酶原激活物受体（uPAR）参与许多生理和病理过程。除了其经典作用外，越来越多的证据表明 uPAR 或与 uPAR 相关的途径参与了中枢神经系统的发育、功能和病理学。在各种癫痫疾病中，无论是在人类还是动物模型中，以及在其他脑部疾病（中风和脑外伤、多发性硬化症、阿尔茨海默病、脑疟疾、HIV 相关的白质脑病和脑炎）中，都观察到 uPAR 和其经典配体 uPA 的表达发生了定性和定量的变化。这些病理状况的多样性以及所涉及的不同大脑区域和细胞类型，可能反映了与 uPAR 相关的多种且相互交织的病理生理机制的广泛和复杂性。在小鼠中，Upar 编码基因（Plaur）的敲除导致脑发育过程中含有副甲状腺素的中间神经元显著且几乎完全缺失。这与自发性和化学诱导性癫痫发作的易感性增加、焦虑增加和社交互动受损有关。新型 uPAR 配体 SRPX2（Sushi 重复蛋白，X 连锁 2）的最新鉴定以及转录因子 FOXP2 对 SRPX2 和 PLAUR 基因的调控，为 uPAR 相关分子网络在 Rolandic 癫痫、发育性言语运动障碍、围脑沟多微小脑回、以及一般言语区域和回路的疾病中的作用提供了新的令人兴奋的见解。uPAR、其调节剂和伙伴，以及其他含有 Ly-6/uPAR/alpha-神经毒素结构域的蛋白质，不仅是目前研究言语相关障碍的关键切入点，也是研究癫痫和自闭症谱系障碍的关键切入点。
