RHEB1 insufficiency in aged male mice is associated with stress-induced seizures.
Qi TianPavel GromovJoachim H ClementYingming WangMarc RiemannFalk WeihXiao-Xin SunMu-Shui DaiLev M FedorovPublished in: GeroScience (2017)
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.
Keyphrases
- stress induced
- cell proliferation
- wild type
- binding protein
- white matter
- protein kinase
- type diabetes
- randomized controlled trial
- resting state
- genome wide
- metabolic syndrome
- gene expression
- transcription factor
- cell therapy
- young adults
- blood brain barrier
- papillary thyroid
- cerebral ischemia
- insulin resistance
- dna methylation
- mesenchymal stem cells
- amino acid
- lymph node metastasis
- subarachnoid hemorrhage