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

Kozo Saito, Eiji Shigetomi, Rei Yasuda, Ryuichi Sato, Masakazu Nakano, Kei Tashiro, Kenji F. Tanaka, Kazuhiro Ikenaka, Katsuhiko Mikoshiba, Ikuko Mizuta, Tomokatsu Yoshida, Masanori Nakagawa, Toshiki Mizuno, Schuichi Koizumi

研究成果: Article査読

15 被引用数 (Scopus)


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 (IP3R2) ameliorated AxD pathogenesis. Taken together, AxCa signals in the model astrocytes would contribute to AxD pathogenesis.

出版ステータスPublished - 2018 5

ASJC Scopus subject areas

  • 神経学
  • 細胞および分子神経科学


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