The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration
Open accessAbstract
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.
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In the citing paper
“Circadian rhythms have been shown to regulate redox homeostasis in the brain, and disruption of circadian genes causes neuronal oxidative damage (Musiek et al., 2013).”
From Clock Genes Control Cortical Critical Period Timing (2015) · cites this paper as Musiek et al., 2013
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In vivo BMAL1 deletion was found to induce activation of glial cells and degeneration of presynaptic axonal terminals.122”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [122]
In the citing paper
“mice with a brain-specific Bmal1 deletion also exhibit increased astrocytosis, despite having mostly normal locomotor circadian rhythms and sleep–wake cycling (that is, relatively normal clock function in the SCN); thus, these neurodegenerative effects are probably due to loss of the local control of cellular metabolism in specific regions of the brain that is normally mediated by BMAL1, indep”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [291]
In the citing paper
“ROS accumulation is considerably higher in Bmal1−/− mice and correlates with increases in astrocytosis and levels of oxidative damage markers in the brain.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [291]
In the citing paper
“Bmal1−/− mice, which lack a functional molecular clock, show premature ageing, neurodegeneration and a reduced lifespan291.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [291]
In the citing paper
“This preclinical investigation demonstrates that components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [291]
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Citations
Cites
Central and Peripheral Circadian Clocks in Mammals
Mohawk, J. A., Green, C. B., & Takahashi, J. S. (2012) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-060909-153128 · Cited by 2,265
Role of the CLOCK Protein in the Mammalian Circadian Mechanism
Gekakis, N., Staknis, D., Nguyen, H. B., Davis, F. C., Wilsbacher, L. D., King, D. P., Takahashi, J. S., & Weitz, C. J. (1998) · Science · doi:10.1126/science.280.5369.1564 · Cited by 2,035
Circadian integration of metabolism and energetics
Bass, J., & Takahashi, J. S. (2010) · Science · doi:10.1126/science.1195027 · Cited by 1,910
Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety
Tronche, F., Kellendonk, C., Kretz, O., Gass, P., Anlag, K., Orban, P. C., Bock, R., Klein, R., & Schütz, G. (1999) · Nature Genetics · doi:10.1038/12703 · Cited by 1,841
Mop3 is an essential component of the master circadian pacemaker in mammals.
Bunger, M. K., Wilsbacher, L. D., Moran, S. M., Clendenin, C., Radcliffe, L. A., Hogenesch, J. B., Simon, M. C., Takahashi, J. S., & Bradfield, C. A. (2000) · Cell · doi:10.1016/s0092-8674(00)00205-1 · Cited by 1,621
Self-citationMolecular analysis of mammalian circadian rhythms
Reppert, S. M., & Weaver, D. R. (2001) · Annual Review of Physiology · doi:10.1146/annurev.physiol.63.1.647 · Cited by 1,444
Self-citationKondratov, R. V., Kondratova, A. A., Gorbacheva, V. Y., Vykhovanets, O. V., & Antoch, M. P. (2006) · Genes & Development · doi:10.1101/gad.1432206 · Cited by 1,188
Hughes, M. E., Hogenesch, J. B., & Kornacker, K. (2010) · Journal of Biological Rhythms · doi:10.1177/0748730410379711 · Cited by 1,087
Self-citationRudic, R. D., McNamara, P., Curtis, A.-M., Boston, R. C., Panda, S., Hogenesch, J. B., & FitzGerald, G. A. (2004) · PLoS Biology · doi:10.1371/journal.pbio.0020377 · Cited by 1,059
Self-citationRegulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors
Rutter, J., Reick, M., Wu, L. C., & McKnight, S. L. (2001) · Science · doi:10.1126/science.1060698 · Cited by 1,059
Cited by
Sorted by citations
A circadian gene expression atlas in mammals: Implications for biology and medicine
Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E., & Hogenesch, J. B. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408886111 · Cited by 2,304
Self-citationRole of neuroinflammation in neurodegeneration development
Zhang, W., Xiao, D., Mao, Q., & Xia, H. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01486-5 · Cited by 1,668
“In vivo BMAL1 deletion was found to induce activation of glial cells and degeneration of presynaptic axonal terminals.(122) Further studies suggested that BMAL1 may affect glial cells activation and neurodegeneration through REV-ERBα, which is a nuclear receptor as well as a circadian clock component that can be induc…”
BackgroundMechanisms linking circadian clocks, sleep, and neurodegeneration
Musiek, E. S., & Holtzman, D. M. (2016) · Science · doi:10.1126/science.aah4968 · Cited by 878
Self-citationRhythms of life: circadian disruption and brain disorders across the lifespan
Logan, R. W., & McClung, C. A. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0088-y · Cited by 713
Association between circadian rhythms and neurodegenerative diseases
Leng, Y., Musiek, E. S., Hu, K., Cappuccio, F. P., & Yaffe, K. S. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30461-7 · Cited by 677
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Metadata
- Authors
- Musiek, E. S., Lim, M. M., Yang, G., Bauer, A. Q., Qi, L., Lee, Y., Roh, J. H., Ortiz-Gonzalez, X., Dearborn, J. T., Culver, J. P., Herzog, E. D., Hogenesch, J. B., Wozniak, D. F., Dikranian, K., Giasson, B. I., Weaver, D. R., Holtzman, D. M., & FitzGerald, G. A.
- Affiliations
- Washington University in St. Louis (US)
- University of Pennsylvania (US)
- University of Florida (US)
- University of Massachusetts Chan Medical School (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2013-11-25
- Volume
- 123
- Issue
- 12
- Pages
- 5389-5400
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3859381
- OpenAlex
- W2003062381
- Cited by
- 524
- References
- 59
- Citations by year
- 2026: 35 · 2025: 54 · 2024: 46 · 2023: 58 · 2022: 53 · 2021: 48 · 2020: 47 · 2019: 34 · 2018: 42 · 2017: 29 · 2016: 30 · 2015: 23 · 2014: 23 · 2013: 2
- FWCI
- 14.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- eScholarship@UMassChan (submittedVersion, other-oa)
- Funders
- Ellison Medical Foundation
- Cure Alzheimer's Fund (P01NS074969)
- Hope Center for Neurological Disorders (P30 NS057105)
- National Institutes of Health (HL097800, NS057105)
- National Institute on Aging (P50AG005681)
- National Heart, Lung, and Blood Institute (HL 097800, R01HL097800)
- National Institute of Neurological Disorders and Stroke (NS-056125, P30NS057105, R01NS078223, K08NS079405, R25NS065745, R01NS056125, P01NS074969)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- circadian clock proteins, Bmal1, clocks, NPAS2, Per1, Per2, redox homeostasis, oxidative stress, neurodegeneration, brain aging, astrocyte activation, synaptic degeneration, cortical functional connectivity, neuronal cell death, striatal degeneration
- MeSH terms
- Aging, Animals, Brain, Cerebral Cortex, Circadian Rhythm, Corpus Striatum, Gene Expression Regulation, Gliosis, Hippocampus, Homeostasis, Locomotion, Mice, Inbred C57BL, Mice, Neurologic Mutants, Nerve Degeneration, Nerve Tissue Proteins, Neuroglia, Neurons, Oxidation-Reduction, Mice, Knockout, Oxidative Stress, Sleep Disorders, Circadian Rhythm, RNA Interference, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, CLOCK Proteins, ARNTL Transcription Factors, Period Circadian Proteins
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