Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex

Abstract

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 or TSC2 genes, which encode proteins that negatively regulate mTOR complex 1 (mTORC1) signaling. Current treatment strategies focus on mTOR inhibition with rapamycin and its derivatives. While effective at improving some aspects of TSC, chronic rapamycin inhibits both mTORC1 and mTORC2 and is associated with systemic side-effects. It is currently unknown which mTOR complex is most relevant for TSC-related brain phenotypes. Here we used genetic strategies to selectively reduce neuronal mTORC1 or mTORC2 activity in mouse models of TSC. We find that reduction of the mTORC1 component Raptor, but not the mTORC2 component Rictor, rebalanced mTOR signaling in Tsc1 knock-out neurons. Raptor reduction was sufficient to improve several TSC-related phenotypes including neuronal hypertrophy, macrocephaly, impaired myelination, network hyperactivity, and premature mortality. Raptor downregulation represents a promising potential therapeutic intervention for the neurological manifestations of TSC.

Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss

“…In contrast, we find that Raptor loss rescues autonomous effects on neuronal morphology and synapse formation and function. This is consistent with the effect of Raptor loss in animal models of Tuberous Sclerosis Complex disorder ( Karalis et al, 2022 ). It is unknown what cellular changes give rise to emergent behavioral changes.…”

“…In addition, previously published results suggest that rapamycin rescues the electrophysiological effects of Pten loss ( Weston et al, 2012 ). The mTORC1 complex is thought to be the primary target of rapamycin; however, rapamycin may also inhibit mTORC2 and other targets ( Karalis et al, 2022 ). We therefore tested whether the rescue of Pten KO phenotype observed with rapamycin treatment was mTORC1 specific.…”

Dual impact of PTEN mutation on CSF dynamics and cortical networks via the dysregulation of neural precursors and their interneuron descendants

“…This study demonstrates mTORC1 as the principal driver of cortical pathology in developing brain structure and function in Pten-mutated CH. However, the contribution of mTOR complex 2 (mTORC2) activation, which may also be inhibited by chronic rapamycin and its analogs 187 , to altered CSF dynamics and brain physiology in Pten mutants was not examined. Future investigations will examine brain structure and function In Pten cKO mice after the deletion of Rictor, the rapamycin-insensitive regulator of mTORC2 activation 188 .…”

Raptor Preys on mTOR Imbalance in Tuberous Sclerosis

“…In this study, Karalis et al dissect the mechanisms of aberrant mTOR signaling in TS and discover that downregulation of mTORC1 protein, Raptor, was effective not only at restoring mTOR balance but also in rescuing some TS phenotypes in a mouse model. 7 To model TS, the authors established primary hippocampal cultures from Tsc1 floxed mice, and then treated the cultured cells with a cre-recombinase-expressing adeno-associated viral construct to delete the floxed Tsc1 gene, as germline Tsc1 deletion is embryonically lethal. Tsc1-cKO cultures exhibited increased levels of mTORC1 proteins Raptor and p-S6, suggesting increased mTORC1 signaling.…”

“…In this study, Karalis et al dissect the mechanisms of aberrant mTOR signaling in TS and discover that downregulation of mTORC1 protein, Raptor, was effective not only at restoring mTOR balance but also in rescuing some TS phenotypes in a mouse model. 7…”