Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs
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...
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Elsevier
2016-11-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716314292 |
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| author | Yoshihito Ishida Hideshi Kawakami Hiroyuki Kitajima Ayaka Nishiyama Yoshiki Sasai Haruhisa Inoue Keiko Muguruma |
| author_facet | Yoshihito Ishida Hideshi Kawakami Hiroyuki Kitajima Ayaka Nishiyama Yoshiki Sasai Haruhisa Inoue Keiko Muguruma |
| author_sort | Yoshihito Ishida |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T08:50:20Z |
| format | Article |
| id | doaj.art-2fde6dc2aea94fb6b00ac3eea83a2817 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-10T08:50:20Z |
| publishDate | 2016-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2fde6dc2aea94fb6b00ac3eea83a28172022-12-22T01:55:35ZengElsevierCell Reports2211-12472016-11-011761482149010.1016/j.celrep.2016.10.026Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCsYoshihito Ishida0Hideshi Kawakami1Hiroyuki Kitajima2Ayaka Nishiyama3Yoshiki Sasai4Haruhisa Inoue5Keiko Muguruma6Laboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental Biology, Kobe 650-0047, JapanDepartment of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, JapanLaboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental Biology, Kobe 650-0047, JapanLaboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe 650-0047, JapanLaboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental Biology, Kobe 650-0047, JapanDepartment of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, JapanLaboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental Biology, Kobe 650-0047, JapanSpinocerebellar 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.http://www.sciencedirect.com/science/article/pii/S2211124716314292spinocerebellar ataxia type 6SCA6Purkinje cellinduced pluripotent stem cellsiPSCsdisease modeling |
| spellingShingle | Yoshihito Ishida Hideshi Kawakami Hiroyuki Kitajima Ayaka Nishiyama Yoshiki Sasai Haruhisa Inoue Keiko Muguruma Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs Cell Reports spinocerebellar ataxia type 6 SCA6 Purkinje cell induced pluripotent stem cells iPSCs disease modeling |
| title | Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs |
| title_full | Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs |
| title_fullStr | Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs |
| title_full_unstemmed | Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs |
| title_short | Vulnerability of Purkinje Cells Generated from Spinocerebellar Ataxia Type 6 Patient-Derived iPSCs |
| title_sort | vulnerability of purkinje cells generated from spinocerebellar ataxia type 6 patient derived ipscs |
| topic | spinocerebellar ataxia type 6 SCA6 Purkinje cell induced pluripotent stem cells iPSCs disease modeling |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716314292 |
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