Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms.
Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms.
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DOI：
10.3389/fnagi.2022.903973
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
--
作者：
Tau是一种微管相关蛋白，已知在生理条件下结合并促进神经元中微管的组装。然而，在病理条件下，过度磷酸化的tau的聚集引起神经元毒性、神经变性和导致的tau蛋白病如阿尔茨海默病（AD）。临床上，患有tau蛋白病的患者表现为痴呆、运动障碍或两者的组合。脑中过度磷酸化tau蛋白的沉积也与多种神经系统疾病中的癫痫和网络过度兴奋相关。此外，基于tau的机制的药理学和遗传靶向可以具有抗癫痫作用。抑制tau磷酸化降低获得性癫痫模型中的癫痫发作活性，而减少或消融tau减弱阿尔茨海默病和癫痫模型中的网络过度兴奋性。然而，目前尚不清楚tau蛋白病和癫痫合并症是否是由癫痫发生和tau聚集上游发生的会聚机制介导的，是由两者之间的前馈机制介导的，还是简单地由同时发生的过程介导的。本文综述了tau蛋白病与癫痫发作的关系，包括颞叶癫痫（TLE）、创伤后癫痫（PTE）、自闭症谱系障碍（ASD）、Dravet综合征、Noding综合征、C型尼曼-皮克病（NPC）、Lafora病、局灶性皮质发育不良和结节性硬化症。我们还探讨了tau激酶和磷酸酶以及哺乳动物雷帕霉素靶蛋白（mTOR）在促进共同病理学中的作用的潜在机制。了解这些共同病理学的作用可能会导致新的见解和针对癫痫机制和认知能力下降的治疗。
Tau is a microtubule-associated protein known to bind and promote assembly of microtubules in neurons under physiological conditions. However, under pathological conditions, aggregation of hyperphosphorylated tau causes neuronal toxicity, neurodegeneration, and resulting tauopathies like Alzheimer’s disease (AD). Clinically, patients with tauopathies present with either dementia, movement disorders, or a combination of both. The deposition of hyperphosphorylated tau in the brain is also associated with epilepsy and network hyperexcitability in a variety of neurological diseases. Furthermore, pharmacological and genetic targeting of tau-based mechanisms can have anti-seizure effects. Suppressing tau phosphorylation decreases seizure activity in acquired epilepsy models while reducing or ablating tau attenuates network hyperexcitability in both Alzheimer’s and epilepsy models. However, it remains unclear whether tauopathy and epilepsy comorbidities are mediated by convergent mechanisms occurring upstream of epileptogenesis and tau aggregation, by feedforward mechanisms between the two, or simply by coincident processes. In this review, we investigate the relationship between tauopathies and seizure disorders, including temporal lobe epilepsy (TLE), post-traumatic epilepsy (PTE), autism spectrum disorder (ASD), Dravet syndrome, Nodding syndrome, Niemann-Pick type C disease (NPC), Lafora disease, focal cortical dysplasia, and tuberous sclerosis complex. We also explore potential mechanisms implicating the role of tau kinases and phosphatases as well as the mammalian target of rapamycin (mTOR) in the promotion of co-pathology. Understanding the role of these co-pathologies could lead to new insights and therapies targeting both epileptogenic mechanisms and cognitive decline.
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