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Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2013 Dec; Vol. 123 (12), pp. 5389-400. Date of Electronic Publication: 2013 Nov 25. - Publication Year :
- 2013
-
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.
- Subjects :
- ARNTL Transcription Factors deficiency
Aging physiology
Animals
Basic Helix-Loop-Helix Transcription Factors deficiency
Brain physiopathology
CLOCK Proteins deficiency
Cerebral Cortex pathology
Circadian Rhythm genetics
Corpus Striatum pathology
Gene Expression Regulation physiology
Gliosis pathology
Hippocampus pathology
Homeostasis genetics
Homeostasis physiology
Locomotion physiology
Mice, Inbred C57BL
Mice, Knockout
Mice, Neurologic Mutants
Nerve Degeneration genetics
Nerve Tissue Proteins deficiency
Neuroglia metabolism
Neuroglia pathology
Neurons pathology
Oxidation-Reduction
Oxidative Stress
Period Circadian Proteins deficiency
Period Circadian Proteins physiology
RNA Interference
Sleep Disorders, Circadian Rhythm physiopathology
ARNTL Transcription Factors physiology
Basic Helix-Loop-Helix Transcription Factors physiology
Brain pathology
CLOCK Proteins physiology
Circadian Rhythm physiology
Gliosis genetics
Nerve Degeneration physiopathology
Nerve Tissue Proteins physiology
Neurons metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 123
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 24270424
- Full Text :
- https://doi.org/10.1172/JCI70317