Murine model of Alexander disease: Analysis of GFAP aggregate formation and its pathological significance

Kenji Tanaka, Hirohide Takebayashi, Yoshihiko Yamazaki, Katsuhiko Ono, Masae Naruse, Takuji Iwasato, Shigeyoshi Itohara, Hiroshi Kato, Kazuhiro Ikenaka

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Alexander disease is caused by a coding mutation in the glial fibrillary acidic protein (GFAP) gene. The pathological hallmark is the formation of cytoplasmic inclusions within astrocytes known as Rosenthal fibers (RFs), which primarily consist of GFAP and several heat shock proteins. The presence of mutant GFAP would appear to be involved in RF formation; however, overproduction of wild type human GFAP in mouse brain also results in RF formation. Here, we investigated the in vivo conditions leading to formation of RF-like aggregates. We used transgenic mice (mouse GFAP promoter-human GFAP cDNA with R239H mutation) in which the dosage of the GFAP transgene could be manipulated within the same genetic locus. We found that the presence of mutant GFAP per se was insufficient for aggregate formation. Instead, a 30% increase in GFAP content over that in wild type was also required. GFAP aggregates upregulated endogenous GFAP and nestin gene expression, and intermediate filament structure revealed by immunostaining was fragmented under these conditions. However, overall morphology of astrocytes, including their fine processes, was unaffected. In this transgenic animal model, mice did not show megalencephaly, leukodystrophy, or seizure characteristic of Alexander disease with R239H mutation. Nevertheless, their mortality after kainate challenge was dramatically increased, whereas transgenic mice lacking aggregates exhibited mortality similar to that of wild type mice. These results indicate that the presence of GFAP aggregates containing mutant GFAP is not sufficient to induce a major phenotype of Alexander disease, even though it causes some abnormalities in the mouse.

Original languageEnglish
Pages (from-to)617-631
Number of pages15
JournalGLIA
Volume55
Issue number6
DOIs
Publication statusPublished - 2007 Apr 15
Externally publishedYes

Fingerprint

Alexander Disease
Glial Fibrillary Acidic Protein
Mutant Proteins
Astrocytes
Protein Aggregates
Mutation
Transgenic Mice
Megalencephaly
Nestin
Genetically Modified Animals
Genetic Loci
Intermediate Filaments
Mortality
Kainic Acid
Inclusion Bodies

Keywords

  • Astrocyte
  • Excitotoxicity
  • Intermediate filament
  • Rosenthal fiber

ASJC Scopus subject areas

  • Immunology

Cite this

Tanaka, K., Takebayashi, H., Yamazaki, Y., Ono, K., Naruse, M., Iwasato, T., ... Ikenaka, K. (2007). Murine model of Alexander disease: Analysis of GFAP aggregate formation and its pathological significance. GLIA, 55(6), 617-631. https://doi.org/10.1002/glia.20486

Murine model of Alexander disease : Analysis of GFAP aggregate formation and its pathological significance. / Tanaka, Kenji; Takebayashi, Hirohide; Yamazaki, Yoshihiko; Ono, Katsuhiko; Naruse, Masae; Iwasato, Takuji; Itohara, Shigeyoshi; Kato, Hiroshi; Ikenaka, Kazuhiro.

In: GLIA, Vol. 55, No. 6, 15.04.2007, p. 617-631.

Research output: Contribution to journalArticle

Tanaka, K, Takebayashi, H, Yamazaki, Y, Ono, K, Naruse, M, Iwasato, T, Itohara, S, Kato, H & Ikenaka, K 2007, 'Murine model of Alexander disease: Analysis of GFAP aggregate formation and its pathological significance', GLIA, vol. 55, no. 6, pp. 617-631. https://doi.org/10.1002/glia.20486
Tanaka, Kenji ; Takebayashi, Hirohide ; Yamazaki, Yoshihiko ; Ono, Katsuhiko ; Naruse, Masae ; Iwasato, Takuji ; Itohara, Shigeyoshi ; Kato, Hiroshi ; Ikenaka, Kazuhiro. / Murine model of Alexander disease : Analysis of GFAP aggregate formation and its pathological significance. In: GLIA. 2007 ; Vol. 55, No. 6. pp. 617-631.
@article{a4be74e1f1f34079a081783b7a37517c,
title = "Murine model of Alexander disease: Analysis of GFAP aggregate formation and its pathological significance",
abstract = "Alexander disease is caused by a coding mutation in the glial fibrillary acidic protein (GFAP) gene. The pathological hallmark is the formation of cytoplasmic inclusions within astrocytes known as Rosenthal fibers (RFs), which primarily consist of GFAP and several heat shock proteins. The presence of mutant GFAP would appear to be involved in RF formation; however, overproduction of wild type human GFAP in mouse brain also results in RF formation. Here, we investigated the in vivo conditions leading to formation of RF-like aggregates. We used transgenic mice (mouse GFAP promoter-human GFAP cDNA with R239H mutation) in which the dosage of the GFAP transgene could be manipulated within the same genetic locus. We found that the presence of mutant GFAP per se was insufficient for aggregate formation. Instead, a 30{\%} increase in GFAP content over that in wild type was also required. GFAP aggregates upregulated endogenous GFAP and nestin gene expression, and intermediate filament structure revealed by immunostaining was fragmented under these conditions. However, overall morphology of astrocytes, including their fine processes, was unaffected. In this transgenic animal model, mice did not show megalencephaly, leukodystrophy, or seizure characteristic of Alexander disease with R239H mutation. Nevertheless, their mortality after kainate challenge was dramatically increased, whereas transgenic mice lacking aggregates exhibited mortality similar to that of wild type mice. These results indicate that the presence of GFAP aggregates containing mutant GFAP is not sufficient to induce a major phenotype of Alexander disease, even though it causes some abnormalities in the mouse.",
keywords = "Astrocyte, Excitotoxicity, Intermediate filament, Rosenthal fiber",
author = "Kenji Tanaka and Hirohide Takebayashi and Yoshihiko Yamazaki and Katsuhiko Ono and Masae Naruse and Takuji Iwasato and Shigeyoshi Itohara and Hiroshi Kato and Kazuhiro Ikenaka",
year = "2007",
month = "4",
day = "15",
doi = "10.1002/glia.20486",
language = "English",
volume = "55",
pages = "617--631",
journal = "GLIA",
issn = "0894-1491",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - Murine model of Alexander disease

T2 - Analysis of GFAP aggregate formation and its pathological significance

AU - Tanaka, Kenji

AU - Takebayashi, Hirohide

AU - Yamazaki, Yoshihiko

AU - Ono, Katsuhiko

AU - Naruse, Masae

AU - Iwasato, Takuji

AU - Itohara, Shigeyoshi

AU - Kato, Hiroshi

AU - Ikenaka, Kazuhiro

PY - 2007/4/15

Y1 - 2007/4/15

N2 - Alexander disease is caused by a coding mutation in the glial fibrillary acidic protein (GFAP) gene. The pathological hallmark is the formation of cytoplasmic inclusions within astrocytes known as Rosenthal fibers (RFs), which primarily consist of GFAP and several heat shock proteins. The presence of mutant GFAP would appear to be involved in RF formation; however, overproduction of wild type human GFAP in mouse brain also results in RF formation. Here, we investigated the in vivo conditions leading to formation of RF-like aggregates. We used transgenic mice (mouse GFAP promoter-human GFAP cDNA with R239H mutation) in which the dosage of the GFAP transgene could be manipulated within the same genetic locus. We found that the presence of mutant GFAP per se was insufficient for aggregate formation. Instead, a 30% increase in GFAP content over that in wild type was also required. GFAP aggregates upregulated endogenous GFAP and nestin gene expression, and intermediate filament structure revealed by immunostaining was fragmented under these conditions. However, overall morphology of astrocytes, including their fine processes, was unaffected. In this transgenic animal model, mice did not show megalencephaly, leukodystrophy, or seizure characteristic of Alexander disease with R239H mutation. Nevertheless, their mortality after kainate challenge was dramatically increased, whereas transgenic mice lacking aggregates exhibited mortality similar to that of wild type mice. These results indicate that the presence of GFAP aggregates containing mutant GFAP is not sufficient to induce a major phenotype of Alexander disease, even though it causes some abnormalities in the mouse.

AB - Alexander disease is caused by a coding mutation in the glial fibrillary acidic protein (GFAP) gene. The pathological hallmark is the formation of cytoplasmic inclusions within astrocytes known as Rosenthal fibers (RFs), which primarily consist of GFAP and several heat shock proteins. The presence of mutant GFAP would appear to be involved in RF formation; however, overproduction of wild type human GFAP in mouse brain also results in RF formation. Here, we investigated the in vivo conditions leading to formation of RF-like aggregates. We used transgenic mice (mouse GFAP promoter-human GFAP cDNA with R239H mutation) in which the dosage of the GFAP transgene could be manipulated within the same genetic locus. We found that the presence of mutant GFAP per se was insufficient for aggregate formation. Instead, a 30% increase in GFAP content over that in wild type was also required. GFAP aggregates upregulated endogenous GFAP and nestin gene expression, and intermediate filament structure revealed by immunostaining was fragmented under these conditions. However, overall morphology of astrocytes, including their fine processes, was unaffected. In this transgenic animal model, mice did not show megalencephaly, leukodystrophy, or seizure characteristic of Alexander disease with R239H mutation. Nevertheless, their mortality after kainate challenge was dramatically increased, whereas transgenic mice lacking aggregates exhibited mortality similar to that of wild type mice. These results indicate that the presence of GFAP aggregates containing mutant GFAP is not sufficient to induce a major phenotype of Alexander disease, even though it causes some abnormalities in the mouse.

KW - Astrocyte

KW - Excitotoxicity

KW - Intermediate filament

KW - Rosenthal fiber

UR - http://www.scopus.com/inward/record.url?scp=33947542997&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33947542997&partnerID=8YFLogxK

U2 - 10.1002/glia.20486

DO - 10.1002/glia.20486

M3 - Article

C2 - 17299771

AN - SCOPUS:33947542997

VL - 55

SP - 617

EP - 631

JO - GLIA

JF - GLIA

SN - 0894-1491

IS - 6

ER -