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

Jonathan O. Lipton, Lara M. Boyle, Elizabeth D. Yuan, Kevin J. Hochstrasser, Fortunate F. Chifamba, Ashwin Nathan, Peter T. Tsai, Fred Davis, Mustafa Sahin

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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. This results in elevated levels of BMAL1 and a dysfunctional clock that displays abnormal timekeeping under constant conditions and exaggerated responses to phase resetting. Genetically lowering the dose of BMAL1 rescues circadian behavioral phenotypes in TSC mouse models. These findings indicate that BMAL1 deregulation is a feature of the mTOR-activated state and suggest a molecular mechanism for mitigating circadian phenotypes in a neurodevelopmental disorder.

Original languageEnglish (US)
Pages (from-to)868-880
Number of pages13
JournalCell Reports
Volume20
Issue number4
DOIs
StatePublished - Jul 25 2017

Fingerprint

Tuberous Sclerosis
Sirolimus
ARNTL Transcription Factors
Clocks
Genes
Phenotype
Deregulation
Autistic Disorder
Circadian Rhythm
Intellectual Disability
Epilepsy
Sleep
Degradation
Mutation
Neurodevelopmental Disorders

Keywords

  • autism
  • BMAL1
  • circadian rhythms
  • mTOR
  • neurodevelopmental disorder
  • sleep disorders
  • translation
  • tuberous sclerosis complex

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lipton, J. O., Boyle, L. M., Yuan, E. D., Hochstrasser, K. J., Chifamba, F. F., Nathan, A., ... Sahin, M. (2017). Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy. Cell Reports, 20(4), 868-880. https://doi.org/10.1016/j.celrep.2017.07.008

Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy. / Lipton, Jonathan O.; Boyle, Lara M.; Yuan, Elizabeth D.; Hochstrasser, Kevin J.; Chifamba, Fortunate F.; Nathan, Ashwin; Tsai, Peter T.; Davis, Fred; Sahin, Mustafa.

In: Cell Reports, Vol. 20, No. 4, 25.07.2017, p. 868-880.

Research output: Contribution to journalArticle

Lipton, JO, Boyle, LM, Yuan, ED, Hochstrasser, KJ, Chifamba, FF, Nathan, A, Tsai, PT, Davis, F & Sahin, M 2017, 'Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy', Cell Reports, vol. 20, no. 4, pp. 868-880. https://doi.org/10.1016/j.celrep.2017.07.008
Lipton JO, Boyle LM, Yuan ED, Hochstrasser KJ, Chifamba FF, Nathan A et al. Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy. Cell Reports. 2017 Jul 25;20(4):868-880. https://doi.org/10.1016/j.celrep.2017.07.008
Lipton, Jonathan O. ; Boyle, Lara M. ; Yuan, Elizabeth D. ; Hochstrasser, Kevin J. ; Chifamba, Fortunate F. ; Nathan, Ashwin ; Tsai, Peter T. ; Davis, Fred ; Sahin, Mustafa. / Aberrant Proteostasis of BMAL1 Underlies Circadian Abnormalities in a Paradigmatic mTOR-opathy. In: Cell Reports. 2017 ; Vol. 20, No. 4. pp. 868-880.
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