Abstract
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 Δ/+) 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 Δ /− hybrid males developed rare stress-induced seizures, whereas Rheb1 +/− and Rheb1 Δ /− females and Rheb1 Δ/+ and Rheb1 Δ/Δ 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.
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Acknowledgements
We are saddened to report that, during the writing of this manuscript, our colleague and co-author Dr. Falk Weih passed away. We gratefully acknowledge Alex Derkatch, Galina Fedorova, and James Smart for the expert technical assistance. We also thank Harald Schubert for providing the laboratory space and T. Gridley for the CJ7 ES cells. We acknowledge the DNA core facility at OHSU for the sequencing analysis. We acknowledge Garet Lahvis and Stephanie Krasnow for their excellent advices. John Crabbe and Pamela Metten are thanked for the helpful discussions and comments on the manuscript. The work was partly supported by Medical Research Foundation (Portland, Oregon), grant no. 9003823, the Office of the Vice President for Research at OHSU, and an NBL-3 grant from Bundesministerium für Bildung und Forschung, Germany.
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Tian, Q., Gromov, P., Clement, J.H. et al. RHEB1 insufficiency in aged male mice is associated with stress-induced seizures. GeroScience 39, 557–570 (2017). https://doi.org/10.1007/s11357-017-9997-3
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DOI: https://doi.org/10.1007/s11357-017-9997-3