期刊
CELL REPORTS
卷 17, 期 6, 页码 1482-1490出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.10.026
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资金
- Program for Intractable Disease Research Utilizing Disease-Specific iPS Cells from the Japan Science and Technology (JST)
- Japan Agency for Medical Research and Development (AMED)
- JSPS KAKENHI [15K07089, 26242085]
- Grants-in-Aid for Scientific Research [26242085, 15K07089] Funding Source: KAKEN
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, alpha 1A 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.
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