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Cited by 21Tuberous Sclerosis Complex ResearchPI3K/AKT/mTOR signaling in cancerGenetics and Neurodevelopmental Disorders

The role of TSC1 and TSC2 proteins in neuronal axons

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Karalis, Vasiliki, Wood, Delaney, Teaney, Nicole A., Sahin, Mustafa·2024·Molecular Psychiatry
DOI 10.1038/s41380-023-02402-7PMC PMC12863650
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Abstract

Tuberous Sclerosis Complex 1 and 2 proteins, TSC1 and TSC2 respectively, participate in a multiprotein complex with a crucial role for the proper development and function of the nervous system. This complex primarily acts as an inhibitor of the mechanistic target of rapamycin (mTOR) kinase, and mutations in either TSC1 or TSC2 cause a neurodevelopmental disorder called Tuberous Sclerosis Complex (TSC). Neurological manifestations of TSC include brain lesions, epilepsy, autism, and intellectual disability. On the cellular level, the TSC/mTOR signaling axis regulates multiple anabolic and catabolic processes, but it is not clear how these processes contribute to specific neurologic phenotypes. Hence, several studies have aimed to elucidate the role of this signaling pathway in neurons. Of particular interest are axons, as axonal defects are associated with severe neurocognitive impairments. Here, we review findings regarding the role of the TSC1/2 protein complex in axons. Specifically, we will discuss how TSC1/2 canonical and non-canonical functions contribute to the formation and integrity of axonal structure and function.

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  • In syndromic forms, mutations in TSC1, TSC2, or PTEN lead to constitutive activation of mTOR signaling, driving aberrant cellular growth and structural brain anomalies.

    “In syndromic forms, mutations in genes such as TSC1, TSC2, or PTEN lead to constitutive activation of mTOR signaling, driving aberrant cellular growth and structural brain anomalies”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Karalis et al., 2024

    The Conclusion and future directions identifies TSC1 and TSC2 loss-of-function mutations as causes of TSC and describes TSC1/2 as an inhibitor of mTOR signaling. The Introduction reports aberrant neuronal growth in TSC models, and the Abstract identifies brain lesions as a manifestation of TSC. The paper does not establish the same chain of effects for PTEN mutations or describe mTOR activation as constitutive; it also notes that some TSC phenotypes may involve mTOR-independent mechanisms. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Karalis, V., Wood, D., Teaney, N. A., & Sahin, M.
Affiliations
Boston Children's Hospital (US)
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2024-01-11
Volume
29
Issue
4
Pages
1165-1178
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-023-02402-7
PMC
PMC12863650
OpenAlex
W4390748434
Cited by
21
References
14
Citations by year
2026: 7 · 2025: 8 · 2024: 6
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (R01NS113591, T32 NS007473)
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
TSC1, TSC2, tuberous sclerosis complex, mTOR signaling, axons, axonal function, neurodevelopmental disorders, epilepsy, intellectual disability, autism spectrum disorder
MeSH terms
Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Axons, Humans, Mutation, Neurons, Tuberous Sclerosis, Signal Transduction, Tumor Suppressor Proteins, TOR Serine-Threonine Kinases

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