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

Area of Science:

• Neuroscience
• Genetics
• Chronobiology

Background:

• Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by TSC1 or TSC2 gene mutations.
• These mutations lead to hyperactivation of the mechanistic target of rapamycin (mTOR) pathway.
• Clinical features include epilepsy, intellectual disability, autism, and sleep disturbances.

Purpose of the Study:

• To investigate the link between TSC, mTOR overactivation, and circadian rhythm abnormalities.
• To elucidate the role of mTOR in regulating core clock proteins, specifically BMAL1.
• To determine if targeting BMAL1 can ameliorate circadian phenotypes in TSC models.

Main Methods:

• Utilized mouse models of Tuberous Sclerosis Complex.
• Investigated the impact of mTOR signaling on BMAL1 proteostasis (translation, degradation, localization).
• Assessed circadian rhythm behavior and timekeeping under constant conditions and after phase-resetting stimuli.
• Genetically reduced BMAL1 levels in TSC mouse models to assess rescue effects.

Main Results:

• TSC mouse models exhibit disrupted circadian rhythms.
• mTOR signaling directly regulates BMAL1 proteostasis, leading to elevated BMAL1 levels.
• Dysfunctional circadian clocks in TSC models show impaired timekeeping and exaggerated responses to phase shifts.
• Reducing BMAL1 dosage genetically rescues circadian behavioral phenotypes in TSC mice.

Conclusions:

• BMAL1 deregulation is a consequence of mTOR overactivation in TSC.
• mTOR-mediated regulation of BMAL1 proteostasis contributes to circadian dysfunction in TSC.
• Targeting BMAL1 presents a potential strategy for mitigating circadian rhythm abnormalities in TSC.