The Circadian Clock as a Capacitor for TSC-related Phenotypes

New therapies for TSC have been hindered by a limited understanding of how the biological causes of the disorder result in its symptoms. While epilepsy, intellectual disability, and autism have been extensively investigated, as a child neurologist and sleep specialist, my laboratory has been trying to understand why patients with TSC commonly have sleep disorders, an aspect of TSC that has received relatively little attention. Through this lens, we have identified a surprisingly direct connection between the biology of TSC and the circadian (circa + dia means ‘about a day’) timekeeping system. The circadian timekeeper is the biological clock that synchronizes us with the earth’s light/dark cycle. While sleepwake cycles are the most obvious manifestation of circadian timing, its control extends far deeper, down to the temporal control of our genes and proteins. We have amassed extensive evidence that identifies a direct biochemical connection between the circadian clock and TSC/mTOR biology. Capitalizing on this data, we offer experimental paradigms to test how the circadian clock can be used as a novel therapeutic approach to TSC by fully assessing how the TSC/mTOR pathways use the clock to control gene expression, protein synthesis, and complex behavior. We believe that our approach is truly novel and that we are uniquely positioned to carry out these potentially translational experiments.