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Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy

Lipton JO, Boyle LM, Yuan ED, Hochstrasser KJ, Chifamba FF, Nathan A, Tsai PT, Davis F, Sahin M · 2017 · Cell Reports · Atlas ID LIP2017

What this study shows

In mouse models of tuberous sclerosis, where mTOR is stuck on, the circadian clock ran abnormally: poor timekeeping in constant conditions and exaggerated responses to phase resetting. mTOR raised BMAL1 levels by changing its translation, degradation and location; genetically lowering BMAL1 rescued the behavioural rhythm defects. Constant, unpatterned mTOR activity disturbs a rhythm downstream.

Abstract

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Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder characterized by mutations in either the TSC1 or TSC2 genes, whose products form a critical inhibitor of the mechanistic target of rapamycin (mTOR). Loss of TSC1/2 gene function renders an mTOR-overactivated state. Clinically, TSC manifests with epilepsy, intellectual disability, autism, and sleep dysfunction. Here, we report that mouse models of TSC have abnormal circadian rhythms. We show that mTOR regulates the proteostasis of the core clock protein BMAL1, affecting its translation, degradation, and subcellular localization.

Read the full abstract on PubMed →

At a glance

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Evidence type A Animal model Marked A because it is an animal intervention or observation study measuring an organismal outcome (model: Mouse models of tuberous sclerosis complex (Tsc1/Tsc2 loss)); the code names the system studied -- animal work can be rigorous and still not be human data.
Study type4 - Animal Study
Model systemMouse models of tuberous sclerosis complex (Tsc1/Tsc2 loss)
JournalCell Reports
Year2017
Peer reviewedYes
Record last updated2026-10-01
SourceDOI 10.1016/j.celrep.2017.07.008 · PMID 28746872 · Free full text (PMC5603761)

Where this study fits

How this study connects to the pathway map, open questions, people and other studies in the Atlas.

People in the Atlas

  • Jonathan O. Lipton first author · 2 studies in the Atlas

    First author of the two studies that tie mTOR signalling to the circadian clock protein BMAL1: S6K1 phosphorylates BMAL1 to drive translation, and constant mTOR activity in tuberous sclerosis disturbs the clock.

  • Mustafa Sahin last author · 3 studies in the Atlas

    Senior author of the studies showing that mTOR signalling reaches the circadian clock through BMAL1, and a physician-scientist focused on tuberous sclerosis, the classic disease of overactive mTOR.

  • Lara M. Boyle 2 studies in the Atlas

    Research assistant at Boston Children's Hospital who co-authored both studies linking mTOR to the clock protein BMAL1, including the tuberous sclerosis study where she was second author.

  • Elizabeth D. Yuan 3 studies in the Atlas

    Second author on the study showing that S6K1 phosphorylates BMAL1 to link mTOR signalling with circadian protein synthesis, and co-author on the follow-up in tuberous sclerosis models.

  • Ashwin Nathan 2 studies in the Atlas

    Co-author on both Boston Children's Hospital studies linking mTOR signalling to the circadian clock protein BMAL1.

More: 4 other authors
  • Peter T. Tsai 2 studies in the Atlas

    Child neurologist and neuroscientist who studies how the cerebellum contributes to autism; first author of the mouse study showing that loss of Tsc1 in Purkinje cells causes autism-like behaviour that rapamycin can prevent.

  • Fred C. Davis 2 studies in the Atlas

    Circadian biologist from Northeastern University who brought expertise on the brain's master clock to two studies linking mTOR and the clock protein BMAL1.

No profile yet: Hochstrasser KJ, Chifamba FF

Related studies

More related studies

All 212 studies on mTORC1

Topics

TSC1/TSC2mTORmTORC1Tuberous sclerosis complex

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

InterventionGenetic loss of Tsc1/Tsc2; reduced Bmal1 dose
TargetmTOR; BMAL1 proteostasis
ModelMouse
EffectmTOR overactivation elevates BMAL1 and disrupts circadian timekeeping; lowering BMAL1 rescues behaviour

Cite this paper

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Lipton, J. O., Boyle, L. M., Yuan, E. D., Hochstrasser, K. J., Chifamba, F. F., Nathan, A., Tsai, P. T., Davis, F., & Sahin, M. (2017). Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy. Cell Reports. https://doi.org/10.1016/j.celrep.2017.07.008

@article{LIP2017,
  author       = {Lipton, J. O. and Boyle, L. M. and Yuan, E. D. and Hochstrasser, K. J. and Chifamba, F. F. and Nathan, A. and Tsai, P. T. and Davis, F. and Sahin, M.},
  title        = {{Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy}},
  journal      = {Cell Reports},
  year         = {2017},
  doi          = {10.1016/j.celrep.2017.07.008},
  note         = {PMID: 28746872},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper. 

Barton, O. (2026). Oliver's mTOR Atlas (record LIP2017) [Data set]. https://mtor-atlas.org/study/LIP2017/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_LIP2017,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record LIP2017},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/LIP2017/},
  doi          = {10.5281/zenodo.22059963}
}
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