Abstract:

Circadian rhythm protects neurons: Although the master clock entrains the whole body rhythm, peripheral tissues also express core clock transcription factors Clock and Bmal1, which regulate expression of clock genes including Period (Per) and Cryptochrome (Cry) proteins. Complexes of Per and Cry proteins repress Bmal1- and Clock-mediated transcription forming a negative feedback loop, which regulates nearly a 24 hours self-sustained rhythm including energy metabolism. Circadian rhythm dysfunction is often observed in patients with Alzheimer’s, Parkinson’s and Huntington’s diseases. Clinical studies and experiments in animal models of neurodegenerative disorders have revealed the progressive nature of circadian dysfunction throughout the course of neurodegeneration. However, the importance of circadian rhythm in the protection of neurons remains to be elucidated.Recent studies suggest that disruption of the circadian rhythm can impair metabolic cooperation between neurons and astrocytes, and thereby enhance oxidative damages in the brain. Thus, understanding the molecular mechanisms by which endogenous antioxidant defense systems are controlled by the circadian rhythm may inform the design of novel therapeutic strategies to protect against neurodegenerative diseases. We recently proposed that neurotrophins activate the redox sensitive transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master regulator of cellular defense against oxidative stress, in a circadian rhythm dependent manner in astrocytes to support neurons in the brain