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

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

来源：Cell Reports, 2017, 20(4): 868-880.

DOI：10.1016/j.celrep.2017.07.008

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.

• 出版日期2017-7-25
• 单位东北大学