title: Modeling Alexander disease with patient iPSCs reveals cellular and molecular pathology of astrocytes.
abstract: Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Misato
authors.initials: M
authors.lastname: Funayama
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Michiyo
authors.initials: M
authors.lastname: Miyake
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tsukita
authors.affiliation: Department of Cell Modulation, Institute of Molecular Embryology and Genetics (iMEG), Kumamoto University, 2-2-1 Honjo, Tyuou-ku, Kumamoto, 860-0811, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Era
authors.affiliation: Department of Pediatrics, Jichi Medical School, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ayaki
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. haruhisa@cira.kyoto-u.ac.jp.
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000328:Adult; D000368:Aged; D038261:Alexander Disease / Q000378:metabolism* / Q000473:pathology*; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002648:Child; D016207:Cytokines / Q000378:metabolism; D055664:Electrochemical Techniques; D005260:Female; D005455:Fluorescent Antibody Technique; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D046228:Microarray Analysis; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D066263:Protein Aggregation, Pathological / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein
keywords: Alexander disease (AxD); Alpha-crystallin; Astrocytes; Cytokine; Disease modeling; Glial fibrillary acidic protein (GFAP); Heat-shock protein; Induced pluripotent stem cells (iPSCs); Inflammatory response; Inherited astrocytopathy; Rosenthal fibers