Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

Erik S. Musiek, Miranda M. Lim, Guangrui Yang, Adam Q. Bauer, Laura Qi, Yool Lee, Jee Hoon Roh, Xilma Ortiz-Gonzalez, Joshua T. Dearborn, Joseph P. Culver, Erik D. Herzog, John B. Hogenesch, David F. Wozniak, Krikor Dikranian, Benoit I. Giasson, David R. Weaver, David M. Holtzman, Garret A. FitzGerald

Research output: Contribution to journalArticle

192 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5389-5400
Number of pages12
JournalJournal of Clinical Investigation
Volume123
Issue number12
DOIs
StatePublished - Dec 2 2013

ASJC Scopus subject areas

  • Medicine(all)

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    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. (2013). Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. Journal of Clinical Investigation, 123(12), 5389-5400. https://doi.org/10.1172/JCI70317