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Aberrant astrocyte Ca 2+ signals “AxCa signals” exacerbate pathological alterations in an Alexander disease model
Author(s) -
Saito Kozo,
Shigetomi Eiji,
Yasuda Rei,
Sato Ryuichi,
Nakano Masakazu,
Tashiro Kei,
Tanaka Kenji F.,
Ikenaka Kazuhiro,
Mikoshiba Katsuhiko,
Mizuta Ikuko,
Yoshida Tomokatsu,
Nakagawa Masanori,
Mizuno Toshiki,
Koizumi Schuichi
Publication year - 2018
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23300
Subject(s) - downregulation and upregulation , astrocyte , glial fibrillary acidic protein , biology , pathogenesis , neuroglia , neuroscience , microbiology and biotechnology , transcriptome , pathology , immunology , gene expression , immunohistochemistry , gene , central nervous system , genetics , medicine
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 Ca 2+ 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 Ca 2+ homeostasis molecules. In situ AxD model astrocytes produced aberrant extra‐large Ca 2+ signals “AxCa signals”, which increased with age, correlated with GFAP upregulation, and were dependent on stored Ca 2+ . 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.