Mind your rhythms: an important role for circadian genes in neuroprotection

Abstract

Circadian rhythms govern nearly every physiological process in our brains and bodies. At the most basic level, the molecular clockwork in each cell interacts with metabolic cycles to influence the redox state, allowing for increased cellular activity at specific times of day. In this issue of the JCI, Musiek et al. show that genetic disruptions in the positive arm of the molecular clock can lead to severe astrogliosis, which likely occurs through disruptions in output genes that keep oxidative stress in check. This study demonstrates the importance of proper circadian protein function in the maintenance of neuronal integrity.

Figure 1. Crosstalk between the transcriptional and peroxiredoxin cycles.

CLOCK or NPAS2 (yellow) and BMAL1 (aqua), which make up the positive limb of the circadian clock, control the expression of negative limb proteins Period (PER) (blue) and cryptochrome (CRY) (orange), which feed back to inhibit the activity of the positive limb. CLOCK(NPAS2)/BMAL1 controls the expression of several output genes (such as Nqo1 and Aldh2) that influence the rhythm in ROS accumulation in the peroxiredoxin cycle. The ratio of NAD(P) to NAD(P)H as an output of this cycle influences SIRT1 (purple) activity (which is NAD⁺ dependent). When bound to NAD⁺, SIRT1 regulates the activity of CLOCK (NPAS2):BMAL1 heterodimers.