Fig. 1From: mTOR inhibitors in the pharmacologic management of tuberous sclerosis complex and their potential role in other rare neurodevelopmental disordersThe mammalian target of rapamycin (mTOR) signaling pathway and possible involvement of rare diseases in the pathway. Stimulants such as insulin-like growth factor bind to tyrosine kinase receptors, which leads to the phosphorylation of phosphatidylinositol 3-kinase (PI3K) [23]. A cascade of subsequent phosphorylation events results in the activation of protein kinase B (AKT), which in turn phosphorylates and inhibits the TSC1/TSC2 complex, a negative regulator of mTOR that is directed against the positive regulator Ras homolog enriched in brain (Rheb). As a result, inhibition of the TSC1/TSC2 complex results in the activation of mTOR [23,24,25]. NF1-encoded neurofibromin and NF2-encoded Merlin proteins also act as negative regulators of the mTOR pathway. Neurofibromin functions as a Ras-GTPase activating protein that inhibits the actions of Ras on PI3K [26], while Merlin acts directly on mTOR complex 1 (mTORC1) [27]. Sirolimus and everolimus both bind to and form complexes with FK506-binding protein-12 (FKBP12), resulting in the inhibition of mTORC1 activity [24]. While mechanisms are complex and not fully clear in Leigh and Down syndrome, evidence has shown a relationship between mTOR activity and ATP (Leigh syndrome), and decreased autophagy with increased protein production and oxidation with mTOR hyperactivation (Down syndrome) [62, 65, 66]Back to article page