Aquaporin-1 (AQP1) is associated with mTOR hyperactivity in tuberous sclerosis complex (TSC)

Hanya Sandel, Roslyn Bill, Philip Kitchen

Aston University, Birmingham, United Kingdom

Tuberous sclerosis complex (TSC) is a rare multisystem genetic disorder caused by mutations in the TSC1 and/or TSC2 genes, which lead to hyperactivity of the mammalian target of rapamycin (mTOR) pathway. Manifestations of TSC include tumour-like lesions in the brain (called tubers) that lead to 90% of patients developing epilepsy. When uncontrolled, the epilepsy can lead to sudden unexpected death in epilepsy (SUDEP), which is the main cause of death for TSC patients. One treatment option for TSC is the use of mTOR inhibitors, such as everolimus. However, while everolimus is effective for halting tumour growth in TSC, efficacy for controlling epilepsy remains variable.

Aquaporins (AQPs) are a family of water channel proteins. 13 human AQPs have been identified (AQP0-AQP12) so far, but little is known about the expression of AQPs in TSC and upon hyperactivity of the mTOR pathway. We have found significant dysregulation of five different AQP genes from RNA-sequencing in tuber samples. Among these, we observe a > 300-fold increase in expression of AQP1. We validated that AQP1 protein expression was also increased in mouse embryonic fibroblasts (MEF) from both TSC1-/- and TSC2-/- mice relative to control. Finally, we have shown that 24-hour treatment with everolimus in the TSC-/- MEF reversed the dysregulation of AQP1 expression. Interestingly, our data also show a significant loss of AQP1 glycosylation in TSC1-/- but not TSC2-/- cells, suggesting a novel role for TSC1 in the regulation of protein glycosylation. Thus, our data indicate a link between mTOR pathway hyperactivity and the regulation of AQP1, with potential implications for AQP1 in the pathogenesis of TSC. Future research will explore dysregulation of AQP1 in TSC resected brain samples from tubers to offer a deeper insight into aquaporin dysregulation in TSC.