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Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells

ABSTRACT: Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells

OTHER RELATED OMICS DATASETS IN: GSE85349

PROVIDER: PRJNA338237 | ENA |

REPOSITORIES: ENA

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Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells [1]

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.

2016-11-08 | E-GEOD-85347 | biostudies-arrayexpress

Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells [1]

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, α1A 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.

2016-11-08 | GSE85347 | GEO

Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells [2]

Project description:Spinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease characterized by loss of Purkinje cells in the cerebellum. It is known to be caused by CAG trinucleotide repeat expansion in CACNA1A, the gene that 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 generation of mature Purkinje cells that carry the patient genes by combining patient-derived iPS cell and self-organizing culture technologies. Patient-derived Purkinje cells exhibited upregulation of whole Cav2.1 protein while downregulation of its C-terminal fragment and the transcriptional targets TAF1 and BTG1. We further demonstrate that patient 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

2016-11-08 | GSE85348 | GEO

Transcriptome analysis of Spinocerebellar Ataxia 17 Aug

Project description:Transcriptome analysis of extracted total RNA from the the cerebellum and muscle of Spinocerebellar Ataxia 17 knock-in mouse model

2015-08-19 | GSE72176 | GEO

Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1

Project description:Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1

| PRJNA503578 | ENA

RNA-seq of Spinocerebellar Ataxia Type2 (SCA2) transgenic mouse lines and age-matched wild-type

Project description:Spinocerebellar ataxia type 2 (SCA2) is among the progressive neurodegenerative polyglutamine (polyQ) diseases. It is caused by a CAG repeat expansion in an encoded region of the ATXN2 gene giving rise to an expanded polyQ domain in the encoded ATXN2 protein. SCA2 is an autosomal dominant disorder characterized by symptoms resulting from neurodegeneration of cerebellar Purkinje cells. To molecularly characterize SCA2 disease progression, we analyzed RNA-sequencing data produced using the cerebella of ATXN2Q127 mice collected at three distinct time points. The ATXN2Q127 mouse model contains 127 CAG repeats in the full-length ATXN2 cDNA under the control of the PC targeted Pcp2 promoter.

2017-12-09 | E-MTAB-6293 | biostudies-arrayexpress

A new Knock-in mouse model of SCA14 with increased PKCγ activity induces a SCA-like phenotype with perturbed Purkinje cell maturation and ataxic motor behavior

Project description:Spinocerebellar ataxias (SCAs) are a group of cerebellar diseases characterized by loss and dysfunction of Purkinje cells and Spinocerebellar ataxia type 14 (SCA14) is caused by missense mutations or deletions in the Protein kinase C γ (PKCγ) gene. Until now, more than 40 different mutations or deletions in the PKCγ gene have been found in SCA14 patients. Many of these mutations have been shown to have an increased enzymatic activity in cell-based assays, but there is also evidence that the mutations may result in inefficient activation of downstream signalling pathways compatible with a loss of function. Therefore, it is still unclear how mutant PKCγ may cause the disease. We have previously generated a transgenic SCA14 mouse model with a human SCA14 mutation in the kinase domain. This transgenic mouse shows mild ataxia and abnormal Purkinje cell dendritic development with a morphology indistinguishable from that of PKC activator treated Purkinje cells, indicating that the PKCγ with this kinase domain mutation has indeed increased biological activity. In order to confirm that increased PKC activity in vivo perturbs Purkinje cell maturation and induces ataxia we have now created a new knock-in mouse model with a missense mutation in the PKCγ pseudosubstrate domain keeping the PKCγ protein in the open active conformation. This knock-in mouse shows indeed abnormal Purkinje cell maturation and ataxia, even in a heterozygous state corresponding to the human disease situation. Our findings confirm that constitutive activation of PKCγ is one way to induce a phenotype corresponding to human spinocerebellar ataxia.

2022-02-24 | PXD019335 | Pride

Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-11-08 | GSE85349 | GEO

Homo sapiens

Project description:Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells [1]

| PRJNA338242 | ENA

Homo sapiens

Project description:Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells [2]

| PRJNA338241 | ENA