Yu Jiangning, Wang Guoxiang, Chen Zhiyun, Wan Li, Zhou Jing, Cai Jingyi, Liu Xu, Wang Yun
Department of Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Rehabilitation Center, Shenzhen Second People's Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen 518035, China.
Hum Mol Genet. 2023 Jan 13;32(3):506-519. doi: 10.1093/hmg/ddac220.
Epilepsy is a chronic neurological disorder featuring recurrent, unprovoked seizures, which affect more than 65 million people worldwide. Here, we discover that the PKHD1L1, which is encoded by polycystic kidney and hepatic disease1-like 1 (Pkhd1l1), wildly distributes in neurons in the central nervous system (CNS) of mice. Disruption of PKHD1L1 in the dentate gyrus region of the hippocampus leads to increased susceptibility to pentylenetetrazol-induced seizures in mice. The disturbance of PKHD1L1 leads to the overactivation of the mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK)-Calpain pathway, which is accompanied by remarkable degradation of cytoplasmic potassium chloride co-transporter 2 (KCC2) level together with the impaired expression and function of membrane KCC2. However, the reduction of membrane KCC2 is associated with the damaged inhibitory ability of the vital GABA receptors, which ultimately leads to the significantly increased susceptibility to epileptic seizures. Our data, thus, indicate for the first time that Pkhd1l1, a newly discovered polycystic kidney disease (PKD) association gene, is required in neurons to maintain neuronal excitability by regulation of KCC2 expression in CNS. A new mechanism of the clinical association between genetic PKD and seizures has been built, which could be a potential therapeutic target for treating PKD-related seizures.
癫痫是一种慢性神经系统疾病，其特征为反复发作的、无端的癫痫发作，全球有超过6500万人受其影响。在此，我们发现由多囊肾和肝病1样1基因（Pkhd1l1）编码的PKHD1L1在小鼠中枢神经系统（CNS）的神经元中广泛分布。海马齿状回区域的PKHD1L1缺失会导致小鼠对戊四氮诱导的癫痫发作的易感性增加。PKHD1L1的紊乱导致丝裂原活化蛋白激酶（MAPK）/细胞外调节激酶（ERK）-钙蛋白酶途径过度激活，同时伴有细胞质氯化钾协同转运蛋白2（KCC2）水平显著降解以及膜KCC2的表达和功能受损。然而，膜KCC2的减少与重要的GABA受体抑制能力受损有关，最终导致癫痫发作的易感性显著增加。因此，我们的数据首次表明，新发现的多囊肾病（PKD）关联基因Pkhd1l1在神经元中是维持神经元兴奋性所必需的，其通过调节中枢神经系统中的KCC2表达来实现。遗传型PKD与癫痫发作之间临床关联的新机制已建立，这可能是治疗PKD相关癫痫发作的潜在治疗靶点。
