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
Affiliations
Brian V. Lananna
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
Collin J. Nadarajah
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
Mariko Izumo
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA
Michelle R. Cedeño
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
David D. Xiong
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
Julie Dimitry
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
Chak Foon Tso
Department of Biology, Washington University, St. Louis, MO, USA
Celia A. McKee
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
Percy Griffin
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
Patrick W. Sheehan
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA
Jeffery A. Haspel
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Ben A. Barres
Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA
Shane A. Liddelow
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
Joseph S. Takahashi
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
Ilia N. Karatsoreos
Integrative Physiology and Neuroscience, College of Veterinary Medicine, Washington State University, Pullman, WA, USA
Erik S. Musiek
Department of Neurology and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USA; Corresponding author
Summary: 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. : Lananna et al. show that the circadian clock protein BMAL1 regulates astrocyte activation via a cell-autonomous mechanism involving diminished glutathione-S-transferase signaling. This finding elucidates a function of the core circadian clock in astrocytes and reveals BMAL1 as a modulator of astrogliosis. Keywords: astrocyte, circadian, astrogliosis, Bmal1, rhythm, neuroinflammation, glutathione
