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Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex
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Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex
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Journal Article
Raptor downregulation rescues neuronal phenotypes in mouse models of Tuberous Sclerosis Complex
2022
Overview
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.
Karalis et al show that genetic reduction of the mTORC1 component Raptor improves multiple phenotypes in mouse models of TSC. Their findings suggest that Raptor could be a potential therapeutic target for treating the neurological aspects of TSC.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 14
/ 14/19
/ 64
/ 64/60
/ 82/1
/ 82/51
/ 96
/ 96/63
/ 96/95
/ Animals
/ Humanities and Social Sciences
/ Kinases
/ Mechanistic Target of Rapamycin Complex 1 - genetics
/ Mechanistic Target of Rapamycin Complex 1 - metabolism
/ Mechanistic Target of Rapamycin Complex 2 - metabolism
/ Mice
/ Mutation
/ Neurodevelopmental disorders
/ Proteins
/ Regulatory-Associated Protein of mTOR - metabolism
/ Science
/ TOR Serine-Threonine Kinases - genetics
/ TOR Serine-Threonine Kinases - metabolism
/ Tuberous Sclerosis - metabolism
