Editors' ChoiceCircadian Rhythms

Mind your bedtime: The circadian clock and mTOR in an orphan brain disease

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Science Translational Medicine  09 Aug 2017:
Vol. 9, Issue 402, eaao2261
DOI: 10.1126/scitranslmed.aao2261


Circadian disturbances that accompany tuberous sclerosis Complex are explored in mouse models.

Orphan diseases are a collection of often devastating maladies that, due to their rarity, have trouble attracting the attention of the biomedical community. Tuberous sclerosis Complex (TSC) is one such orphan disease, in which benign tumors gradually develop throughout the bodies of young children. When these growths accumulate in the central nervous system, the result is hard-to-control seizures and cognitive impairment. Circadian rhythm disruption like abnormal sleep is also common in TSC patients, although whether this is a consequence of tumor growth is unclear. The genetics of TSC are now well understood and involve mutations in the genes tsc1 and tsc2, which repress a key nutrient sensor called the mechanistic target of rapamycin (mTOR). In a recent paper, Lipton et al. used mouse models to explain how mutations in tsc1 and tsc2 lead to aberrant circadian rhythms. They show that mutations in tsc1 or tsc2 lead to excess mTOR activity, which in turn produces increased levels of BMAL1 protein, a key constituent of the circadian clock. The effect of mTOR on BMAL1 appears to be mediated not by gene expression but by increasing the rate of BMAL1 protein synthesis and also reducing the rate of its degradation. Importantly, they show that directly reducing BMAL1 abundance through hemizygous gene deletion is enough to restore normal circadian rhythms in tsc2 mutant mice, despite the fact that these mice still develop other neurological symptoms of TSC. Although circadian disruption is not the most pressing clinical issue for TSC sufferers, the results of Lipton et al. are important because they explain an “orphaned” aspect of this orphan disease that creates difficulty for afflicted children and their families. The authors also note that circadian disruption is a facet of other, more common neurodevelopmental diseases like autism. As such, targeting mTOR and BMAL1 activities could yield benefits that extend well beyond rare diseases like TSC.

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