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Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration
Erik S. Musiek, … , David M. Holtzman, Garret A. FitzGerald
Erik S. Musiek, … , David M. Holtzman, Garret A. FitzGerald
Published November 25, 2013
Citation Information: J Clin Invest. 2013;123(12):5389-5400. https://doi.org/10.1172/JCI70317.
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Research Article

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

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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

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

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Figure 7

Diminished Bmal1 expression enhances neurodegeneration.

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Diminished Bmal1 expression enhances neurodegeneration.
 
(A and B). Bma...
(A and B). Bmal1 knockdown in primary neuronal cultures induces neuronal death. (A) Representative phase-contrast photomicrographs from DIV 7 mouse cortical neuron–enriched cultures 5 days after treatment with LV expressing scrambled shRNA (LV-scr) or BMAL1 shRNA (LV-shBMAL1) and after 24 hours of treatment with vehicle (Con) or H2O2. Original magnification, ×10. (B) Quantification of cell viability as assessed by MTT assay. Data are representative of three independent experiments. (C) siRNA-mediated knockdown of Bmal1 in primary astrocyte cultures does not induce astrocyte activation or suppress Nqo1 or Aldh2 transcription. mRNA levels quantified by qPCR and normalized to 18S rRNA. Data are expressed as fold change from sister cultures transfected with scrambled siRNA. The mean ± SEM of four separate experiments is shown. *P < 0.05 by 1-way ANOVA with Bonferroni’s post test. (D and E) Representative photomicrographs showing area of striatal neurodegeneration (dotted line) in WT (D) and Bmal1 hemizygous (E) mice 3 days after intrastriatal injection of 3-NP. Scale bar: 250 μm. (F) Quantification of 3-NP striatal lesion volume as assessed by cresyl violet staining. *P < 0.05 by 2-way ANOVA with a Bonferroni’s post test, as compared with control condition. het, heterodimer.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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