Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1

Brian V Lananna; Collin J Nadarajah; Mariko Izumo; Michelle R Cedeño; David D Xiong; Julie Dimitry; Chak Foon Tso; Celia A McKee; Percy Griffin; Patrick W Sheehan; Jeffery A Haspel; Ben A Barres; Shane A Liddelow; Joseph S Takahashi; Ilia N Karatsoreos; Erik S Musiek

doi:10.1016/j.celrep.2018.09.015

Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1

Cell Rep. 2018 Oct 2;25(1):1-9.e5. doi: 10.1016/j.celrep.2018.09.015.

Authors

Brian V Lananna¹, Collin J Nadarajah¹, Mariko Izumo², Michelle R Cedeño¹, David D Xiong¹, Julie Dimitry¹, Chak Foon Tso³, Celia A McKee¹, Percy Griffin¹, Patrick W Sheehan¹, Jeffery A Haspel⁴, Ben A Barres⁵, Shane A Liddelow⁶, Joseph S Takahashi⁷, Ilia N Karatsoreos⁸, Erik S Musiek⁹

Affiliations

¹ Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA.
² Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³ Department of Biology, Washington University, St. Louis, MO, USA.
⁴ Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
⁵ Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA.
⁶ Neuroscience Institute, Department of Neuroscience and Physiology, NYU Langone Medical Center, New York, NY, USA; Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC, Australia.
⁷ Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁸ Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, WA, USA.
⁹ Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA. Electronic address: [email protected].

Abstract

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism and a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation and inflammatory gene expression in vitro and in vivo, mediated in part by suppression of glutathione-S-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a mechanism by which the circadian clock could influence many aspects of brain function and neurological disease.

Keywords: Bmal1; astrocyte; astrogliosis; circadian; glutathione; neuroinflammation; rhythm.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ARNTL Transcription Factors
Animals
Astrocytes / cytology
Astrocytes / metabolism*
Cell Death / physiology
Circadian Clocks / genetics
Circadian Clocks / physiology*
Female
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Primary Cell Culture
Transfection

Substances

ARNTL Transcription Factors
Bmal1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding