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 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.
Laboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan; Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan; Drug Discovery & Disease Research Laboratory, Shionogi & Co., Ltd., Osaka 561-0825, Japan.
Yoshihito
Y
Ishida
Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
Hideshi
H
Kawakami
Laboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
Hiroyuki
H
Kitajima
Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
Ayaka
A
Nishiyama
Laboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
Yoshiki
Y
Sasai
Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
Haruhisa
H
Inoue
Laboratory for Organogenesis and Neurogenesis, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan; Laboratory for Cell Asymmetry, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan. Electronic address: muguruma@cdb.riken.jp.
Keiko
K
Muguruma
D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000072417:Protein Domains; D011689:Purkinje Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019782:Riluzole / Q000494:pharmacology; D020754:Spinocerebellar Ataxias / Q000473:pathology*; D013972:Thyrotropin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D020864:Calcium Channels, N-Type; D019782:Riluzole; D013972:Thyrotropin
Purkinje cell; SCA6; disease modeling; iPSCs; induced pluripotent stem cells; spinocerebellar ataxia type 6