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CACNA1A loss-of-function mutations affect neurogenesis in different ways in human iPSC-derived neural models

ABSTRACT: CACNA1A encodes the pore-forming α1A subunit of CaV2.1 calcium channel, whose altered function is associated with different neurological disorders including variable forms of ataxia, epilepsy, and migraine. In this study, we generated isogenic iPSC-derived neural cultures carrying two CACNA1A loss-of-function variants differently affecting CaV2.1 isoforms. Morphological, molecular, and functional assays highlighted distinct neurodevelopmental defects. F1491S mutation, which is located in a constitutive domain of the channel, impaired neural induction at very early stages, as demonstrated by changes in migratory capacity and single-cell transcriptomic signatures in neural progenitors, and by defective polarization in neurons. Instead, cells carrying Y1854X mutation, which selectively affects the [EFa] isoform, behaved normally in terms of neural induction but showed altered neuronal network composition and lack of synchronized activity. Our findings highlighted important roles of CACNA1A in mechanisms underlying early neural induction, neuronal maturation, and neural network dynamics.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276494 | GEO | 2025/02/03

REPOSITORIES: GEO

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RNA profiling by deepSAGE sequencing in the cortex of a migraine mouse model after induction of cortical spreading depression

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Project 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, ?1A subunit of P/Q-type calcium channel. However, the pathogenic mechanism and effective therapeutic treatments are still unknown. Here we have succeeded in generation of differentiated Purkinje cells that carry the patient genes by combining disease-specific iPS cells and self-organizing culture technologies. SCA6-iPS cells derived Purkinje cells exhibited increased level of whole Cav2.1 protein while decreased level 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 would be useful for pathogenic investigation and drug screening. Examination of mRNA profile in 1 ES cell line, two healthy donnor-derived iPS cell lines, three case-derived iPS cell lines and 1 normal dermal fibroblasts.

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CACNA1A loss-of-function mutations affect neurogenesis in different ways in human iPSC-derived neural models

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