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Cited by 40Tuberous Sclerosis Complex ResearchPI3K/AKT/mTOR signaling in cancerGenetics and Neurodevelopmental Disorders

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

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Karalis, Vasiliki, Caval-Holme, Franklin, Bateup, Helen S.·2022·Nature Communications
DOI 10.1038/s41467-022-31961-6PMC PMC9363483

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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.

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  • TSC1-TSC2 loss affects neuronal development and properties.

    “In addition, whereas this work highlights astrocytes, we also observed transcriptomic changes in neurons, and considerable previous work has shown that TSC1–TSC2 loss affects neuronal development and properties11,13,35,55,56,57.”

    From mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis (2026) · cites this paper as [13]

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Authors
Karalis, V., Caval-Holme, F., & Bateup, H. S.
Affiliations
  • University of California, Berkeley (US)
  • Chan Zuckerberg Biohub San Francisco (US)
Corresponding author
Bateup, Helen S.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-08-09
Volume
13
Issue
1
Pages
4665-4665
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-31961-6
PMC
PMC9363483
OpenAlex
W4290793632
Cited by
40
References
106
Citations by year
2026: 6 · 2025: 7 · 2024: 15 · 2023: 10 · 2022: 2
FWCI
5.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (T32GM7232-40)
  • U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS105634)
  • Research grants from the Mary Elizabeth Rennie Foundation for Epilepsy Research and Chan Zuckerberg Biohub.
Topics
  • Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
tuberous sclerosis complex, raptors, mTORC1, mTORC2, Rictor, neuronal hypertrophy, macrocephaly, myelination, premature mortality, mTOR signaling, therapeutic target
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Regulatory-Associated Protein of mTOR, Mechanistic Target of Rapamycin Complex 2, Animals, Disease Models, Animal, Neurons, Tuberous Sclerosis, Down-Regulation, Sirolimus, Mice, TOR Serine-Threonine Kinases

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