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

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. [Display omitted] •TSC mouse models and cells demonstrate abnormal circadian behavior and physiology•Increased BMAL1 protein in Tsc knockout cells and animals results from defective proteostasis•Genetically lowering BMAL1 expression rescued circadian phenotypes in Tsc2+/− mice Sleep disorders are common in neurodevelopmental disorders such as the tuberous sclerosis complex (TSC). Lipton et al. demonstrate that increased translation and decreased degradation of the core clock protein BMAL1 underlie circadian rhythm abnormalities in TSC mouse and cellular models.