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PO1-1-106

Aberrant astrocyte Ca2+ signals “AxCa signals” exacerbate pathological alterations in an Alexander disease model

[Speaker] Kozo Saito:1,2
[Co-author] Eiji Shigetomi:2, Rei Yasuda:1, Ryuichi Sato:3, Kenji F Tanaka:4,5, Katsuhiko Mikoshiba:6, Ikuko Mizuta:1, Tomokatsu Yoshida:1, Toshiki Mizuno:1, Schuichi Koizumi:2
1:Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan, 2:Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Japan, 3:Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Japan, 4:Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Japan, 5:Department of Neuropsychiatry, Keio University School of Medicine, Japan, 6:Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Japan

Alexander disease (AxD) is a rare neurodegenerative disorder caused by gain of function mutations in the glial fibrillary acidic protein (GFAP) gene. Accumulation of GFAP proteins and formation of Rosenthal fibers (RFs) in astrocytes are hallmarks of AxD. However, malfunction of astrocytes in the AxD brain is poorly understood. Here, we show aberrant Ca2+ responses in astrocytes as playing a causative role in AxD. Transcriptome analysis of astrocytes from a model of AxD showed age-dependent upregulation of GFAP, several markers for neurotoxic reactive astrocytes, and downregulation of Ca2+ homeostasis molecules. In situ AxD model astrocytes produced aberrant extra-large Ca2+ signals "AxCa signals", which increased with age, correlated with GFAP upregulation, and were dependent on stored Ca2+. Inhibition of AxCa signals by deletion of inositol 1,4,5-trisphosphate type 2 receptors ameliorated AxD pathogenesis. Taken together, AxCa signals in the model astrocytes would be a cause of AxD pathogenesis.
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