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 Tanaka, Kazuhiro Ikenaka, Katsuhiko Mikoshiba, Ikuko Mizuta, Tomokatsu Yoshida, Masanori Nakagawa, Toshiki Mizuno, Schuichi Koizumi

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournalGLIA
DOIs
Publication statusAccepted/In press - 2018 Jan 1

Fingerprint

Alexander Disease
Astrocytes
Glial Fibrillary Acidic Protein
Up-Regulation
Inositol 1,4,5-Trisphosphate Receptors
Gene Expression Profiling
Neurodegenerative Diseases
Homeostasis
Down-Regulation

Keywords

  • Alexander disease
  • Astrocyte
  • AxCa signals
  • GFAP
  • IPR2

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Saito, K., Shigetomi, E., Yasuda, R., Sato, R., Nakano, M., Tashiro, K., ... Koizumi, S. (Accepted/In press). Aberrant astrocyte Ca2+ signals "AxCa signals" exacerbate pathological alterations in an alexander disease model. GLIA. https://doi.org/10.1002/glia.23300

Aberrant astrocyte Ca2+ signals "AxCa signals" exacerbate pathological alterations in an alexander disease model. / Saito, Kozo; Shigetomi, Eiji; Yasuda, Rei; Sato, Ryuichi; Nakano, Masakazu; Tashiro, Kei; Tanaka, Kenji; Ikenaka, Kazuhiro; Mikoshiba, Katsuhiko; Mizuta, Ikuko; Yoshida, Tomokatsu; Nakagawa, Masanori; Mizuno, Toshiki; Koizumi, Schuichi.

In: GLIA, 01.01.2018.

Research output: Contribution to journalArticle

Saito, K, Shigetomi, E, Yasuda, R, Sato, R, Nakano, M, Tashiro, K, Tanaka, K, Ikenaka, K, Mikoshiba, K, Mizuta, I, Yoshida, T, Nakagawa, M, Mizuno, T & Koizumi, S 2018, 'Aberrant astrocyte Ca2+ signals "AxCa signals" exacerbate pathological alterations in an alexander disease model', GLIA. https://doi.org/10.1002/glia.23300
Saito, Kozo ; Shigetomi, Eiji ; Yasuda, Rei ; Sato, Ryuichi ; Nakano, Masakazu ; Tashiro, Kei ; Tanaka, Kenji ; Ikenaka, Kazuhiro ; Mikoshiba, Katsuhiko ; Mizuta, Ikuko ; Yoshida, Tomokatsu ; Nakagawa, Masanori ; Mizuno, Toshiki ; Koizumi, Schuichi. / Aberrant astrocyte Ca2+ signals "AxCa signals" exacerbate pathological alterations in an alexander disease model. In: GLIA. 2018.
@article{8437e52c14be4c53946cba9144c51d77,
title = "Aberrant astrocyte Ca2+ signals {"}AxCa signals{"} exacerbate pathological alterations in an alexander disease model",
abstract = "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.",
keywords = "Alexander disease, Astrocyte, AxCa signals, GFAP, IPR2",
author = "Kozo Saito and Eiji Shigetomi and Rei Yasuda and Ryuichi Sato and Masakazu Nakano and Kei Tashiro and Kenji Tanaka and Kazuhiro Ikenaka and Katsuhiko Mikoshiba and Ikuko Mizuta and Tomokatsu Yoshida and Masanori Nakagawa and Toshiki Mizuno and Schuichi Koizumi",
year = "2018",
month = "1",
day = "1",
doi = "10.1002/glia.23300",
language = "English",
journal = "GLIA",
issn = "0894-1491",
publisher = "John Wiley and Sons Inc.",

}

TY - JOUR

T1 - Aberrant astrocyte Ca2+ signals "AxCa signals" exacerbate pathological alterations in an alexander disease model

AU - Saito, Kozo

AU - Shigetomi, Eiji

AU - Yasuda, Rei

AU - Sato, Ryuichi

AU - Nakano, Masakazu

AU - Tashiro, Kei

AU - Tanaka, Kenji

AU - Ikenaka, Kazuhiro

AU - Mikoshiba, Katsuhiko

AU - Mizuta, Ikuko

AU - Yoshida, Tomokatsu

AU - Nakagawa, Masanori

AU - Mizuno, Toshiki

AU - Koizumi, Schuichi

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Alexander disease

KW - Astrocyte

KW - AxCa signals

KW - GFAP

KW - IPR2

UR - http://www.scopus.com/inward/record.url?scp=85041234725&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041234725&partnerID=8YFLogxK

U2 - 10.1002/glia.23300

DO - 10.1002/glia.23300

M3 - Article

C2 - 29383757

AN - SCOPUS:85041234725

JO - GLIA

JF - GLIA

SN - 0894-1491

ER -