Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish.
Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish.
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DOI：
10.1002/acn3.542
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发表时间：
2018-05
影响因子：
5.3
通讯作者：
Ciura S
中科院分区：
文献类型：
--
作者：
de Calbiac H;Dabacan A;Marsan E;Tostivint H;Devienne G;Ishida S;Leguern E;Baulac S;Muresan RC;Kabashi E;Ciura S
DEPDC5被确定为局灶性癫痫的主要遗传原因，在广泛的遗传性局灶性癫痫中发现有害突变，在某些情况下与皮质发育畸形有关。移码、截短和缺失突变的鉴定与局灶性癫痫病因中DEPDC5的单倍性不足有关。DEPDC5是GATOR1复合体的一个组成部分，作为mTOR信号的负调控因子。斑马鱼是一种适合用于癫痫相关疾病遗传分析和药物筛选的脊椎动物模型。在本研究中，我们定义了depdc5在发育过程中的表达，并建立了depdc5表达降低的癫痫模型。在这里，我们报告了斑马鱼的Depdc5功能丧失模型，该模型显示出可测量的行为表型，包括运动亢进、绕圈游泳和神经元活动增加。这些表型特征在整个胚胎发育过程中持续存在，并在使用mTORC1抑制剂雷帕霉素以及人WT DEPDC5转录物过表达后显著减少。在表达癫痫相关的DEPDC5突变（p.a g487*和p.a g485gln）时，没有获得表型拯救，表明这些突变导致该蛋白的功能丧失。该研究表明，Depdc5基因敲低可导致与运动和神经元过度活跃相关的早期表型特征。通过WT而不是癫痫相关的Depdc5突变体以及mTORC1抑制恢复表型特征，证实了Depdc5在mTORC1依赖的分子级联反应中的作用，将这一途径定义为Depdc5遗传性局灶性癫痫的潜在治疗靶点。
DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling. Zebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy‐related disorders. In this study, we defined the expression of depdc5 during development and established an epilepsy model with reduced Depdc5 expression. Here we report a zebrafish model of Depdc5 loss‐of‐function that displays a measurable behavioral phenotype, including hyperkinesia, circular swimming, and increased neuronal activity. These phenotypic features persisted throughout embryonic development and were significantly reduced upon treatment with the mTORC1 inhibitor, rapamycin, as well as overexpression of human WT DEPDC5 transcript. No phenotypic rescue was obtained upon expression of epilepsy‐associated DEPDC5 mutations (p.Arg487* and p.Arg485Gln), indicating that these mutations cause a loss of function of the protein. This study demonstrates that Depdc5 knockdown leads to early‐onset phenotypic features related to motor and neuronal hyperactivity. Restoration of phenotypic features by WT but not epilepsy‐associated Depdc5 mutants, as well as by mTORC1 inhibition confirm the role of Depdc5 in the mTORC1‐dependent molecular cascades, defining this pathway as a potential therapeutic target for DEPDC5‐inherited forms of focal epilepsy.
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影响因子：
3.7
作者：
Grone BP;Marchese M;Hamling KR;Kumar MG;Krasniak CS;Sicca F;Santorelli FM;Patel M;Baraban SC
通讯作者：
Baraban SC
影响因子：
5.6
作者：
Korenke, Georg-Christoph;Eggert, Marlene;Steinlein, Ortrud K.
通讯作者：
Steinlein, Ortrud K.
影响因子：
2.5
作者：
KIMMEL, CB;BALLARD, WW;SCHILLING, TF
通讯作者：
SCHILLING, TF
影响因子：
11.2
作者：
Baulac, Stephanie;Ishida, Saeko;Picard, Fabienne
通讯作者：
Picard, Fabienne
影响因子：
9.9
作者：
Picard, Fabienne;Makrythanasis, Periklis;Baulac, Stephanie
通讯作者：
Baulac, Stephanie