Mechanistic target of rapamycin (mTOR) forms two multiprotein complexes, mTOR complex 1 (TORC1) and mTOR complex 2 (TORC2) that play multiple roles in cellular metabolism.
mTOR is well known to oncologists. It has been implicated in multiple cancers and it the target of therapies, such as temsirolimus and everolimus. The mTORC1 complex responds to multiple signals, and when activated, changes the cell metabolism from catabolic to anabolic program, thus promoting protein synthesis and cell growth while repressing autophagy. A growing body of literature has shown that mTORC1 plays an important role in the pathology of lysosomal storage diseases (LSDs). The major cellular clearance pathway for organelles and unwanted proteins is the autophagy-lysosome pathway; and mTORC1 plays a crucial role in the lysosomal function by regulating their biogenesis, distribution, and activity. It also modulates autophagy and it has been suggested that abnormal lysosomal function leads to activation of autophagy by mTOR downregulation. Results from several studies have demonstrated clear links between lysosomal dysfunction and mTORC1 activity. There is mTOR pathway dysfunction in sphingolipidoses, which has been demonstrated in peripheral blood mononuclear cells derived from patients with Gaucher and Fabry diseases, which leads to impaired autophagy. Dysfunction of the autophagy-lysosomal pathway has also been shown to be a key pathogenic event in neurodegeneration associated with GBA mutations that give rise to Gaucher disease. Lysosomal alterations in Gaucher disease neurons are linked to dysfunction of the transcription factor EB (TFEB). TFEB controls the coordinated expression of autophagy and lysosomal genes and is negatively regulated by mTORC1. Correction of mTORC1 hyperactivity in these neurons upregulates lysosomal biogenesis and enhances autophagic clearance in Gaucher disease neurons. These results have prompted the suggestion that the mTOR complex may be a therapeutic target for treatment of neurodegeneration in Gaucher disease. Experiments in muscle cell culture and an animal model of Pompe disease have shown that diseased muscle cells are characterized by decreased mTOR activity. Impaired mTOR reactivation and defective lysosome reformation have also been observed in fibroblasts from patients with Scheie syndrome and Fabry disease. All of these results suggest that either up- or down-regulation of mTORC1 activity may occur in patients with LSDs and that modulation of this complex could be an important adjunct to existing treatments for these diseases.