GATOR1 complex: the common genetic actor in focal epilepsies
GATOR1 complex: the common genetic actor in focal epilepsies
复制标题
DOI：
10.1136/jmedgenet-2016-103883
复制
发表时间：
2016-08-01
影响因子：
4
通讯作者：
Pippucci, Tommaso
中科院分区：
文献类型：
--
作者：
Baldassari, Sara;Licchetta, Laura;Pippucci, Tommaso
雷帕霉素（mTOR）信号通路的哺乳动物或机制靶点在调节全身，特别是大脑的生理方面具有多种作用。解除mTOR信号的管制与包括癫痫在内的各种神经系统疾病有关。编码Gap活性通向破布1 （GATOR1）组分（DEPDC5， NPRL2和NPRL3）的基因突变，一种参与抑制mTOR复合物1 （mTORC1）的复合物，最近被认为与广谱局灶性癫痫（FEs）的发病机制有关，包括病变性和非病变性。大约10%的FEs中涉及到DEPDC5、NPRL2和NRPL3，这与特定癫痫符号学指出主要涉及特定大脑区域的概念相反。假设癫痫的致病机制是GATOR1对mTORC1抑制功能的丧失。确定FE患者的正确治疗策略是具有挑战性的，特别是那些患有难治性癫痫和/或皮质发育畸形（MCDs）的患者。在这种情况下，手术切除癫痫区是一种治疗选择，尽管长期结果仍不确定。由于mTOR通路基因突变，GATOR1/mTOR信号在FEs中是一个有希望的治疗靶点，如结节性硬化症，另一种由mTOR信号过度激活引起的mcd相关癫痫。
The mammalian or mechanistic target of rapamycin (mTOR) signalling pathway has multiple roles in regulating physiology of the whole body and, particularly, the brain. Deregulation of mTOR signalling has been associated to various neurological conditions, including epilepsy. Mutations in genes encoding components of Gap Activity TOward Rags 1 (GATOR1) (DEPDC5, NPRL2 and NPRL3), a complex involved in the inhibition of the mTOR complex 1 (mTORC1), have been recently implicated in the pathogenesis of a wide spectrum of focal epilepsies (FEs), both lesional and non-lesional. The involvement of DEPDC5, NPRL2 and NRPL3 in about 10% of FEs is in contrast to the concept that specific seizure semiology points to the main involvement of a distinct brain area. The hypothesised pathogenic mechanism underlying epilepsy is the loss of the inhibitory function of GATOR1 towards mTORC1. The identification of the correct therapeutic strategy in patients with FE is challenging, especially in those with refractory epilepsy and/or malformations of cortical development (MCDs). In such cases, surgical excision of the epileptogenic zone is a curative option, although the long-term outcome is still undefined. The GATOR1/mTOR signalling represents a promising therapeutic target in FEs due to mutations in mTOR pathway genes, as in tuberous sclerosis complex, another MCD-associated epilepsy caused by mTOR signalling hyperactivation.