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Modeling Alexander disease with patient iPSCs reveals cellular and molecular pathology of astrocytes.

Kondo T, Funayama M, Miyake M, Tsukita K, Era T, Osaka H, Ayaki T, Takahashi R, Inoue H - Acta Neuropathol Commun (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

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.

No MeSH data available.


Related in: MedlinePlus

Gene expression comparison between healthy control and Alexander’s disease astrocytes. a Scatter plot showing the 2-fold upregulated and downregulated genes (red and blue dots, respectively) in the astrocytes of Alexander disease. b List of increased and decreased top-20 genes (red and blue columns, respectively)
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Fig5: Gene expression comparison between healthy control and Alexander’s disease astrocytes. a Scatter plot showing the 2-fold upregulated and downregulated genes (red and blue dots, respectively) in the astrocytes of Alexander disease. b List of increased and decreased top-20 genes (red and blue columns, respectively)

Mentions: To uncover molecules involved in the AxD astrocyte pathogenesis, we analyzed global gene expression profiles of iPSC-derived astrocytes (Fig. 5a and b). Among 40,716 probe sets, we created a gene set with altered expression in AxD astrocytes versus control astrocytes (fold-change ≥ 2 fold). By adapting this gene set to the pathway analysis software, we investigated the background pathway of the AxD pathomechanism. Pathway analysis revealed altered function of cellular adherence (Additional file 2: Figure S2) and transcription change via mTORC1/mTORC2 (Additional file 3: Figure S3).Fig. 5


Modeling Alexander disease with patient iPSCs reveals cellular and molecular pathology of astrocytes.

Kondo T, Funayama M, Miyake M, Tsukita K, Era T, Osaka H, Ayaki T, Takahashi R, Inoue H - Acta Neuropathol Commun (2016)

Gene expression comparison between healthy control and Alexander’s disease astrocytes. a Scatter plot showing the 2-fold upregulated and downregulated genes (red and blue dots, respectively) in the astrocytes of Alexander disease. b List of increased and decreased top-20 genes (red and blue columns, respectively)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940830&req=5

Fig5: Gene expression comparison between healthy control and Alexander’s disease astrocytes. a Scatter plot showing the 2-fold upregulated and downregulated genes (red and blue dots, respectively) in the astrocytes of Alexander disease. b List of increased and decreased top-20 genes (red and blue columns, respectively)
Mentions: To uncover molecules involved in the AxD astrocyte pathogenesis, we analyzed global gene expression profiles of iPSC-derived astrocytes (Fig. 5a and b). Among 40,716 probe sets, we created a gene set with altered expression in AxD astrocytes versus control astrocytes (fold-change ≥ 2 fold). By adapting this gene set to the pathway analysis software, we investigated the background pathway of the AxD pathomechanism. Pathway analysis revealed altered function of cellular adherence (Additional file 2: Figure S2) and transcription change via mTORC1/mTORC2 (Additional file 3: Figure S3).Fig. 5

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

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.

No MeSH data available.


Related in: MedlinePlus