Figure 3. Circadian-regulated pathways essential to NDDs.

At the beginning of the cycle, CLOCK and BMAL1 protein complexes bind DNA at specific promoter regions (E-box) to activate the transcription of a family of genes including the Period (Per1, Per2, and Per3) and Cryptochrome (Cry1 and Cry2) genes. The levels of the transcripts for Per and Cry reach their peak during mid- to late day, while the PER and CRY proteins peak in the early night. The PERs, CRYs, and other proteins form complexes that translocate back into the nucleus and turn off the transcriptional activity driven by CLOCK-BMAL1 with a delay (due to transcription, translation, dimerization, and nuclear entry). The proteins would be degraded by ubiquitination, allowing the cycle to begin again. Many cells contain this molecular feedback loop that regulates the rhythmic transcription of a number of genes. Other feedback loops within the cells serve to contribute to the precision and robustness of the core oscillation. Of particular importance, a rhythm in the transcription of BMAL1 is driven by a secondary feedback loop involving the activator retinoic acid receptor–related orphan receptor (ROR) and the repressor REV-ERBα/β. Mechanistically, this circadian clockwork drives a number of processes implicated in NDD. For example, the circadian clock regulates a number of pathways involved in proteostasis, including molecular chaperones as well as autophagy. In addition, many of the genes involved in control of excitability and secretion are rhythmically regulated by this molecular feedback loop. While the precise mechanisms involved in the transmission of misfolded proteins are not known, they are likely impacted by circadian disruption. Finally, it has long been appreciated that there is a close relationship between the circadian clock and the immune system, and disruptions of the circadian timing system drive neuroinflammation, mediated by glial cells. CCGs, circadian clock genes; RORE, ROR response element.