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Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex
Vasiliki Karalis1, Franklin Caval-Holme2, Helen S Bateup3,4,5
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, 94720, USA.
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.
Insights
Targeting the mTORC1 pathway component Raptor, not mTORC2, improved neurological symptoms in Tuberous Sclerosis Complex (TSC) mouse models. This suggests Raptor downregulation is a promising therapeutic strategy for TSC brain phenotypes.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Tuberous Sclerosis Complex (TSC) is a genetic neurodevelopmental disorder linked to mTORC1 signaling dysregulation.
- Current treatments like rapamycin broadly inhibit mTORC1/mTORC2, causing side effects and unclear efficacy for neurological symptoms.
- The specific mTOR complex driving TSC brain phenotypes remains unidentified.
Purpose of the Study:
- To investigate the differential roles of mTORC1 and mTORC2 in TSC-related neurological phenotypes.
- To determine if selective modulation of mTORC1 or mTORC2 can ameliorate TSC brain manifestations.
- To evaluate Raptor (mTORC1 component) and Rictor (mTORC2 component) as therapeutic targets.
Main Methods:
- Utilized genetic strategies in mouse models to selectively reduce neuronal mTORC1 or mTORC2 activity.
- Compared the effects of reducing Raptor (mTORC1) versus Rictor (mTORC2) in Tsc1 knockout neurons.
- Assessed TSC-related phenotypes including neuronal size, brain size, myelination, network activity, and survival.
Main Results:
- Selective reduction of Raptor (mTORC1) rebalanced mTOR signaling in Tsc1 knockout neurons.
- Raptor downregulation, but not Rictor reduction, significantly improved neuronal hypertrophy, macrocephaly, and impaired myelination.
- Raptor reduction also mitigated network hyperactivity and extended survival in TSC mouse models.
Conclusions:
- Neuronal mTORC1 signaling, specifically via Raptor, is critically involved in TSC-related brain phenotypes.
- Targeting Raptor offers a potential therapeutic strategy to address the neurological aspects of TSC with potentially fewer systemic side effects than broad mTOR inhibitors.
- Selective mTORC1 modulation represents a promising avenue for treating TSC neurological manifestations.
