RHEB1 insufficiency in aged male mice is associated with stress-induced seizures.
RHEB1 insufficiency in aged male mice is associated with stress-induced seizures.
复制标题
老年雄性小鼠的 RHEB1 不足与应激诱发的癫痫发作有关。
DOI：
10.1007/s11357-017-9997-3
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发表时间：
2017
期刊：
影响因子：
5.6
通讯作者：
Fedorov,LevM
中科院分区：
文献类型：
--
作者：
Tian,Qi;Gromov,Pavel;Clement,JoachimH;Wang,Yingming;Riemann,Marc;Weih,Falk;Sun,Xiao-Xin;Dai,Mu-Shui;Fedorov,LevM
The mechanistic target of rapamycin (mTOR), a protein kinase, is a central regulator of mammalian metabolism and physiology. Protein mTOR complex 1 (mTORC1) functions as a major sensor for the nutrient, energy, and redox state of a cell and is activated by ras homolog enriched in brain (RHEB1), a GTP-binding protein. Increased activation of mTORC1 pathway has been associated with developmental abnormalities, certain form of epilepsy (tuberous sclerosis), and cancer. Clinically, those mTOR-related disorders are treated with the mTOR inhibitor rapamycin and its rapalogs. Because the effects of chronic interference with mTOR signaling in the aged brain are yet unknown, we used a genetic strategy to interfere with mTORC1 signaling selectively by introducing mutations ofRheb1into the mouse. We created conventional knockout (Rheb1+/−) and gene trap (Rheb1Δ/+) mutant mouse lines.Rheb1-insufficient mice with different combinations of mutant alleles were monitored over a time span of 2 years. The mice did not show any behavioral/neurological changes during the first 18 months of age. However, after aging (> 18 months of age), both theRheb1+/−andRheb1Δ /−hybrid males developed rare stress-induced seizures, whereasRheb1+/−andRheb1Δ /−females andRheb1Δ/+andRheb1Δ/Δmice of both genders did not show any abnormality. Our findings suggest that chronic intervention with mTORC1 signaling in the aged brain might be associated with major adverse events.
