Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350108, China.
Fuzhou Children's Hospital of Fujian Medical University, Fuzhou, Fujian, 350005, China.
Cereb Cortex. 2021 May 10;31(6):3082-3095. doi: 10.1093/cercor/bhab004.
Pin1 is a unique isomerase that regulates protein conformation and function after phosphorylation. Pin1 aberration contributes to some neurological diseases, notably Alzheimer's disease, but its role in epilepsy is not fully understood. We found that Pin1-deficient mice had significantly increased seizure susceptibility in multiple chemical inducing models and developed age-dependent spontaneous epilepsy. Electrophysiologically, Pin1 ablation enhanced excitatory synaptic transmission to prefrontal cortex (PFC) pyramidal neurons without affecting their intrinsic excitability. Biochemically, Pin1 ablation upregulated AMPA receptors and GluA1 phosphorylation by acting on phosphorylated CaMKII. Clinically, Pin1 was decreased significantly, whereas phosphorylated CaMKII and GluA1 were increased in the neocortex of patients with epilepsy. Moreover, Pin1 expression restoration in the PFC of Pin1-deficient mice using viral gene transfer significantly reduced phosphorylated CaMKII and GluA1 and effectively suppressed their seizure susceptibility. Thus, Pin1-CaMKII-AMPA receptors are a novel axis controlling epileptic susceptibility, highlighting attractive new therapeutic strategies.
Pin1 是一种独特的异构酶，在磷酸化后调节蛋白质构象和功能。Pin1 异常导致一些神经退行性疾病，特别是阿尔茨海默病，但它在癫痫中的作用尚不完全清楚。我们发现 Pin1 缺陷小鼠在多种化学诱导模型中癫痫易感性显著增加，并出现年龄依赖性自发性癫痫。电生理学研究表明，Pin1 缺失增强了前额叶皮质（PFC）锥体神经元的兴奋性突触传递，而不影响其内在兴奋性。生物化学研究表明，Pin1 通过作用于磷酸化的 CaMKII 而上调 AMPA 受体和 GluA1 磷酸化。临床研究表明，癫痫患者大脑新皮层中 Pin1 明显减少，而磷酸化的 CaMKII 和 GluA1 增加。此外，通过病毒基因转移在 Pin1 缺陷小鼠的 PFC 中恢复 Pin1 表达可显著降低磷酸化的 CaMKII 和 GluA1，有效抑制其癫痫易感性。因此，Pin1-CaMKII-AMPA 受体是控制癫痫易感性的新轴，为治疗提供了新的策略。
