title: Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration.
abstract: 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.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Musiek
authors.forename: Miranda M
authors.initials: MM
authors.lastname: Lim
authors.forename: Guangrui
authors.initials: G
authors.lastname: Yang
authors.forename: Adam Q
authors.initials: AQ
authors.lastname: Bauer
authors.forename: Laura
authors.initials: L
authors.lastname: Qi
authors.forename: Yool
authors.initials: Y
authors.lastname: Lee
authors.forename: Jee Hoon
authors.initials: JH
authors.lastname: Roh
authors.forename: Xilma
authors.initials: X
authors.lastname: Ortiz-Gonzalez
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Dearborn
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Culver
authors.forename: Erik D
authors.initials: ED
authors.lastname: Herzog
authors.forename: John B
authors.initials: JB
authors.lastname: Hogenesch
authors.forename: David F
authors.initials: DF
authors.lastname: Wozniak
authors.forename: Krikor
authors.initials: K
authors.lastname: Dikranian
authors.forename: Benoit I
authors.initials: BI
authors.lastname: Giasson
authors.forename: David R
authors.initials: DR
authors.lastname: Weaver
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: Garret A
authors.initials: GA
authors.lastname: Fitzgerald
mesh_terms: D056930:ARNTL Transcription Factors / Q000172:deficiency / Q000502:physiology*; D000375:Aging / Q000502:physiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000502:physiology*; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D056926:CLOCK Proteins / Q000172:deficiency / Q000502:physiology*; D002540:Cerebral Cortex / Q000473:pathology; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D003342:Corpus Striatum / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology; D005911:Gliosis / Q000235:genetics* / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology; D008124:Locomotion / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009410:Nerve Degeneration / Q000235:genetics / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D056950:Period Circadian Proteins / Q000172:deficiency / Q000502:physiology; D034622:RNA Interference; D020178:Sleep Disorders, Circadian Rhythm / Q000503:physiopathology
chemical_list: D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D056926:CLOCK Proteins; D009419:Nerve Tissue Proteins; D056950:Period Circadian Proteins; C538961:Bmal1 protein, mouse; C491259:Npas2 protein, mouse; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; C538944:Clock protein, mouse