RHEB1 insufficiency in aged male mice is associated with stress-induced seizures

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 ) 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 hybrid males developed rare stress-induced seizures, whereas Rheb1 and Rheb1 females and Rheb1 and Rheb1 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.

Age-related alterations of articular cartilage in pituitary adenylate cyclase–activating polypeptide (PACAP) gene–deficient mice

“…Deficient PACAP-signaling was found in various neurodegenerative diseases such as Alzheimer’s disease (Wu et al 2006) and Parkinson’s disease (Feher et al 2018). Furthermore, reduced metabolism is detected in aging process (LaRoche et al 2018; Nacarelli et al 2018; Tian et al 2017) which can be compensated by PACAP (Mansouri et al 2016). Aging can lead to several skeletal and oral diseases such as dental root caries or alveolar bone loss (An et al 2018); on the other hand, PACAP regulates the development of teeth (Fulop et al 2018).…”

Rapamycin and Rapalogs

“…Once mTORC1 is localized to the lysosome, its activation depends upon interaction with Rheb-GTP; however, in the presence of the Tuberous Sclerosis Complex (TSC), which acts as a GAP for Rheb, Rheb is found bound GDP. The activity of TSC is controlled by many different kinases, including AKT, AMPK, CDK4/6, ERK, GSK3 and IKKβ, which phosphorylate different residues and proteins within the TSC complex (138,(142)(143)(144)(145)(146)(147)(148). In the absence of insulin/PI3K/AKT signaling, TSC localizes to the lysosome; when AKT is activated, it phosphorylates TSC on multiple residues, and TSC departs from the lysosome, which allows Rheb to be loaded with GTP (149).…”

Lysosome: The metabolic signaling hub

“…The TSC complex acts as a GAP for Rheb, and acts as a “mini” signaling hub upstream of mTORC1 95 . Many different kinases, including AKT, AMPK, ERK, GSK3, and IKKβ phosphorylate distinct residues of TSC1 and TSC2, and thereby serve to regulate mTORC1 by altering the GAP activity of TSC towards Rheb 95–101 . While it was originally thought that these posttranslational modifications directly altered the activity of TSC, it was recently shown that much like mTORC1 and Rheb, TSC is also regulated by localization.…”

“…95 Many different kinases, including AKT, AMPK, ERK, GSK3 and IKKβ, phosphorylate distinct residues of TSC1 and TSC2, and thereby serve to regulate mTORC1 by altering the GAP activity of TSC toward Rheb. [95][96][97][98][99][100][101] While it was originally thought that these posttranslational modifications directly altered the activity of TSC, it was recently shown that much like mTORC1 and Rheb, TSC is also regulated by localization. In the absence of insulin signaling, TSC is localized to the lysosome, where it can directly inhibit Rheb.…”