| First Author | Tian Q | Year | 2017 |
| Journal | Geroscience | Volume | 39 |
| Issue | 5-6 | Pages | 557-570 |
| PubMed ID | 28891034 | Mgi Jnum | J:254122 |
| Mgi Id | MGI:6111417 | Doi | 10.1007/s11357-017-9997-3 |
| Citation | Tian Q, et al. (2017) RHEB1 insufficiency in aged male mice is associated with stress-induced seizures. Geroscience 39(5-6):557-570 |
| abstractText | 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 of Rheb1 into the mouse. We created conventional knockout (Rheb1 (+/-) ) and gene trap (Rheb1 (Delta/+) ) 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 the Rheb1 (+/-) and Rheb1 (Delta /-) hybrid males developed rare stress-induced seizures, whereas Rheb1 (+/-) and Rheb1 (Delta /-) females and Rheb1 (Delta/+) and Rheb1 (Delta/Delta) mice 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. |
