Department of Neurobiology; Weaver Lab
Medical Subject Headings
ARNTL Transcription Factors; Aging; Animals; Basic Helix-Loop-Helix Transcription Factors; Brain; CLOCK Proteins; Cerebral Cortex; Circadian Rhythm; Corpus Striatum; Gene Expression Regulation; Gliosis; Hippocampus; Homeostasis; Locomotion; Mice, Inbred C57BL; Mice, Knockout; Mice, Neurologic Mutants; Nerve Degeneration; Nerve Tissue Proteins; Neuroglia; Neurons; Oxidation-Reduction; Oxidative Stress; Period Circadian Proteins; RNA Interference; Sleep Disorders, Circadian Rhythm
Neuroscience and Neurobiology
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.
Rights and Permissions
Citation: J Clin Invest. 2013 Dec;123(12):5389-400. doi: 10.1172/JCI70317. Epub 2013 Nov 25. Link to article on publisher's website
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Musiek, Erik S.; Weaver, David R.; Holtzman, David M.; and Fitzgerald, Garret A., "Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration" (2013). Neurobiology Publications and Presentations. 151.