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j.celrep.2016.10.026.pdf | 4.28 MB | Adobe PDF | 見る/開く |
タイトル: | Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs |
著者: | Ishida, Yoshihito Kawakami, Hideshi Kitajima, Hiroyuki Nishiyama, Ayaka Sasai, Yoshiki Inoue, Haruhisa https://orcid.org/0000-0003-4736-9537 (unconfirmed) Muguruma, Keiko |
キーワード: | spinocerebellar ataxia type 6 SCA6 Purkinje cell induced pluripotent stem cells iPSCs disease modeling |
発行日: | 1-Nov-2016 |
出版者: | Elsevier BV |
誌名: | Cell Reports |
巻: | 17 |
号: | 6 |
開始ページ: | 1482 |
終了ページ: | 1490 |
抄録: | Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease characterized by loss of Purkinje cells in the cerebellum. SCA6 is caused by CAG trinucleotide repeat expansion in CACNA1A, which encodes Cav2.1, α1A subunit of P/Q-type calcium channel. However, the pathogenic mechanism and effective therapeutic treatments are still unknown. Here, we have succeeded in generating differentiated Purkinje cells that carry patient genes by combining disease-specific iPSCs and self-organizing culture technologies. Patient-derived Purkinje cells exhibit increased levels of full-length Cav2.1 protein but decreased levels of its C-terminal fragment and downregulation of the transcriptional targets TAF1 and BTG1. We further demonstrate that SCA6 Purkinje cells exhibit thyroid hormone depletion-dependent degeneration, which can be suppressed by two compounds, thyroid releasing hormone and Riluzole. Thus, we have constructed an in vitro disease model recapitulating both ontogenesis and pathogenesis. This model may be useful for pathogenic investigation and drug screening. |
著作権等: | © 2016 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
URI: | http://hdl.handle.net/2433/219643 |
DOI(出版社版): | 10.1016/j.celrep.2016.10.026 |
PubMed ID: | 27806289 |
出現コレクション: | 学術雑誌掲載論文等 |
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