TY - JOUR AU - Musiek, Erik S. AU - Lim, Miranda M. AU - Yang, Guangrui AU - Bauer, Adam Q. AU - Qi, Laura AU - Lee, Yool AU - Roh, Jee Hoon AU - Ortiz-Gonzalez, Xilma AU - Dearborn, Joshua T. AU - Culver, Joseph P. AU - Herzog, Erik D. AU - Hogenesch, John B. AU - Wozniak, David F. AU - Dikranian, Krikor AU - Giasson, Benoit I. AU - Weaver, David R. AU - Holtzman, David M. AU - FitzGerald, Garret A. T1 - Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration PY - 2013/12/02/ AB - Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator–like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI70317 VL - 123 IS - 12 UR - https://doi.org/10.1172/JCI70317 SP - 5389 EP - 5400 PB - The American Society for Clinical Investigation ER -