实验模型和人类癫痫中癫痫灶的 Fyn-tau 和 NR2B-PSD95 相互作用增强。

IF 4.1 Q1 CLINICAL NEUROLOGY Brain communications Pub Date : 2024-09-19 eCollection Date: 2024-01-01 DOI:10.1093/braincomms/fcae327
Marson Putra, Nikhil S Rao, Cara Gardner, Guanghao Liu, Jordan Trommater, Michael Bunney, Meghan Gage, Alexander G Bassuk, Marco Hefti, Gloria Lee, Thimmasettappa Thippeswamy
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引用次数: 0

摘要

癫痫和阿尔茨海默病有一些共同的病理特征,如神经变性、癫痫发作和认知能力受损。然而,这些变化的分子机制在很大程度上仍然未知。Fyn是一种Src家族非受体酪氨酸激酶(SFK),它与tau的相互作用介导了癫痫和阿尔茨海默病的脑部病理变化,可以成为改变疾病的潜在治疗靶点。虽然阿尔茨海默病和癫痫都会出现 Fyn 和 tau 病理变化,但 Fyn-tau 和 PSD95-NR2B 的相互作用受癫痫发作影响的动态及其对癫痫脑病理变化的影响尚未得到研究。在本研究中,我们证明了在急性和慢性啮齿动物模型以及人类癫痫中,凯因特诱导癫痫发作后 Fyn-tau 相互作用的显著增加。在癫痫发生的早期阶段,我们发现癫痫状态后 Fyn/tau/NR2B/PSD95/ 神经元一氧化氮合酶复合物增加,突触后磷酸化 tau(pY18 和 AT8)、Fyn(pSFK-Y416)、NMDAR(pNR2B-Y1472)和神经元一氧化氮合酶增加。海马邻近结扎试验和共免疫沉淀显示,大鼠慢性癫痫患者在癫痫发作后 3 个月,Fyn-tau 和 NR2B-PSD95 复合物/结合持续增加。Fyn-tau复合物的增强与慢性癫痫模型中自发复发的抽搐发作和癫痫样棘波的频率密切相关。在人类癫痫患者的大脑中,我们还发现了增加的 Fyn-tau 和 NR2B-PSD95 复合物、tau 磷酸化(pY18 和 AT8)和 Fyn 激活(pSFK-Y416),这意味着这些分子相互作用具有转化和治疗潜力。在用Fyn/SFK抑制剂沙拉替尼治疗的tau基因敲除小鼠和大鼠中,我们发现磷酸化的Fyn、tau(沙拉替尼治疗组为AT8)、NR2B和神经元一氧化氮合酶及其相互作用(沙拉替尼治疗组为Fyn-tau和NR2B-PSD95;tau基因敲除组为NR2B-PSD95)显著减少。与药物治疗组相比,沙拉卡替尼治疗组中Fyn-tau和NR2B-PSD95相互作用的减少与大鼠慢性癫痫模型中癫痫发作进展的改变相关。这些来自动物模型和人类癫痫的研究结果为Fyn-tau和NR2B-PSD95相互作用在癫痫发作诱导的脑病理学中的作用提供了证据,并表明阻断这种相互作用可以改变癫痫的进展。
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Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy.

Epilepsy and Alzheimer's disease share some common pathologies such as neurodegeneration, seizures and impaired cognition. However, the molecular mechanisms of these changes are still largely unknown. Fyn, a Src-family non-receptor tyrosine kinase (SFK), and its interaction with tau in mediating brain pathology in epilepsy and Alzheimer's disease can be a potential therapeutic target for disease modification. Although Fyn and tau pathology occurs in both Alzheimer's disease and epilepsy, the dynamics of Fyn-tau and PSD95-NR2B interactions affected by seizures and their impact on brain pathology in epilepsy have not been investigated. In this study, we demonstrate a significant increase of Fyn-tau interactions following seizure induction by kainate in both acute and chronic rodent models and in human epilepsy. In the early phase of epileptogenesis, we show increased Fyn/tau/NR2B/PSD95/neuronal nitric oxide synthase complexes after status epilepticus and a postsynaptic increase of phosphorylated tau (pY18 and AT8), Fyn (pSFK-Y416), NMDAR (pNR2B-Y1472) and neuronal nitric oxide synthase. Hippocampal proximity ligation assay and co-immunoprecipitation revealed a sustained increase of Fyn-tau and NR2B-PSD95 complexes/binding in rat chronic epilepsy at 3 months post-status epilepticus. Enhanced Fyn-tau complexes strongly correlated with the frequency of spontaneously recurring convulsive seizures and epileptiform spikes in the chronic epilepsy model. In human epileptic brains, we also identified increased Fyn-tau and NR2B-PSD95 complexes, tau phosphorylation (pY18 and AT8) and Fyn activation (pSFK-Y416), implying the translational and therapeutic potential of these molecular interactions. In tau knockout mice and in rats treated with a Fyn/SFK inhibitor saracatinib, we found a significant reduction of phosphorylated Fyn, tau (AT8 in saracatinib-treated), NR2B and neuronal nitric oxide synthase and their interactions (Fyn-tau and NR2B-PSD95 in saracatinib-treated group; NR2B-PSD95 in tau knockout group). The reduction of Fyn-tau and NR2B-PSD95 interactions in the saracatinib-treated group, in contrast to the vehicle-treated group, correlated with the modification in seizure progression in the rat chronic epilepsy model. These findings from animal models and human epilepsy provide evidence for the role of Fyn-tau and NR2B-PSD95 interactions in seizure-induced brain pathology and suggest that blocking such interactions could modify the progression of epilepsy.

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