The paradox of autophagy in Tuberous Sclerosis Complex

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by germline mutations in TSC1 or TSC2 genes, which leads to the hyperactivation of the mTORC1 pathway, an important negative regulator of autophagy. This leads to the development of hamartomas in multiple organs. The variability in symptoms presents a challenge for the development of completely effective treatments for TSC. One option is the treatment with mTORC1 inhibitors, which are targeted to block cell growth and restore autophagy. However, the therapeutic effect of rapamycin seems to be more efficient in the early stages of hamartoma development, an effect that seems to be associated with the paradoxical role of autophagy in tumor establishment. Under normal conditions, autophagy is directly inhibited by mTORC1. In situations of bioenergetics stress, mTORC1 releases the Ulk1 complex and initiates the autophagy process. In this way, autophagy promotes the survival of established tumors by supplying metabolic precursors during nutrient deprivation; paradoxically, excessive autophagy has been associated with cell death in some situations. In spite of its paradoxical role, autophagy is an alternative therapeutic strategy that could be explored in TSC. This review compiles the findings related to autophagy and the new therapeutic strategies targeting this pathway in TSC.

The multifaceted role of autophagy in cancer

“…PI3K signaling promotes AKT‐mediated phosphorylation and inactivation of the tuberous sclerosis complex (TSC), thus relieving the inhibitory effect of TSC on mTORC1. Analysis of precancerous lesions from patients harboring TSC mutations revealed a repression of autophagy, which was reversible upon pharmacological mTORC1 inhibition (Reis et al , 2021).…”

Decanoic Acid Stimulates Autophagy in D. discoideum

“…Autophagy has a recognized role in epilepsy that was first established when rapamycin, an autophagy inducer, was shown to suppress seizures [ 1 ]. Subsequently, a blockage in autophagy has been identified in patients with genetic conditions giving rise to seizures, such as tuberous sclerosis complex (TSC) [ 65 , 66 ] and Lafora disease [ 4 ]. Thus, novel approaches are currently being examined to activate autophagy as a treatment for epilepsy [ 2 , 67 , 68 ].…”

Beyond Protein Synthesis; The Multifaceted Roles of Tuberin in Cell Cycle Regulation

“…Similarly, autophagy induced due to low energy/nutrients levels can be initiated through AMPK phosphorylation of Tuberin and subsequent mTORC1 inhibition (Kim et al, 2011), but it can also be triggered independent of Tuberin via direct phosphorylation of Raptor by AMPK (Gwinn et al, 2008). The roles for Tuberin in autophagy appear to be important in normal development and to also be implicated in disease states such as TSC and cancer (Parkhitko et al, 2011;Reis et al, 2021).…”