Homo sapiens
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: GSE85349
PROVIDER: PRJNA338241 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells
| PRJNA338237 | ENA
Project description:Vulnerability of Purkinje cells induced from spinocerebellar ataxia type 6 patient-derived iPS cells [1]
| PRJNA338242 | ENA
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
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
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
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
Project description:Spinocerebellar ataxia type 1 (SCA1) is a polyglutamine (polyQ) repeat neurodegenerative disease in which a primary site of pathogenesis are cerebellar Purkinje cells. In addition to polyQ expansion of ataxin-1 protein (ATXN1), phosphorylation of ATXN1 at the serine 776 residue (ATXN1-pS776) plays a significant role in protein toxicity. Utilizing a biochemical approach, pharmacological agents and cell-based assays, including SCA1 patient iPSC-derived neurons, we examine the role of Protein Kinase A (PKA) as an effector of ATXN1-S776 phosphorylation. We further examine the implications of PKA-mediated phosphorylation at ATXN1-S776 on SCA1 through genetic manipulation of the PKA catalytic subunit Cα in Pcp2-ATXN1[82Q] mice. Here we show that pharmacologic inhibition of S776 phosphorylation in transfected cells and SCA1 patient iPSC-derived neuronal cells lead to a decrease in ATXN1. In vivo, reduction of PKA-mediated ATXN1-pS776 results in enhanced degradation of ATXN1 and improved cerebellar-dependent motor performance. These results provide evidence that PKA is a biologically important kinase for ATXN1-pS776 in cerebellar Purkinje cells.
2019-05-31 | GSE114815 | GEO
Project description:Disease-specific induced pluripotent stem (iPS) cells have been used for a model to analyze pathogenesis of the disease. We generated iPS cells derived from a fibroblastic cell line of ataxia telangiectasia (AT-iPS cells). In analysis of AT-iPS cells, the human wild-type iPS cell line (MRC5-iPS) was generated and cultured in the same conditions as the diseased iPS cell lines. It is an ideal control cell line for the disease and patient-specific iPS cell lines. Because MRC5-iPS cells exhibited considerable chromosomal abnormalities in vitro, we performed a structural alteration analysis by using a SNP genotyping array for MRC5-iPS cell line, Tic, at passage 15, passage 30, and passage 37.
2013-07-23 | GSE49082 | GEO
Project description:Polyglutamine(polyQ) expansion of α1A voltage-dependent calcium channel (Cav2.1) is the causative mutation of spinocerebellar ataxia type 6 (SCA6). The C-terminal fragment (CTF) of Cav2.1 makes aggregates in the cytoplasm of SCA6 Purkinje cells and may relate to the pathogenesis. In order to identify genes associated with polyQ expansion and subcellular localization of CTF, we analyzed gene expression profiles of PC12 rat pheochromocytoma cells using Tet-off system.
2013-03-13 | GSE26933 | GEO
Project description:Genome instability is a potential limitation to the research and therapeutic application of induced pluripotent stem cells (iPSCs). Observed genomic variations reflect the combined activities of DNA damage, cellular DNA damage response (DDR), and selection pressure in culture. To understand the contribution of DDR on the distribution of copy number variations (CNVs) in iPSCs, we mapped CNVs of iPSCs with mutations in the central DDR gene ATM onto genome organization landscapes defined by genome-wide replication timing profiles. We show that following reprogramming the early and late replicating genome is differentially affected by CNVs in ATM deficient iPSCs relative to wild type iPSCs. Specifically, the early replicating regions had increased CNV losses during retroviral reprogramming. This differential CNV distribution was not present after later passage or after episomal reprogramming. Comparison of different reprogramming methods in the setting of defective DNA damage response reveals unique vulnerability of early replicating open chromatin to retroviral vectors. We isolated RNA from Ataxia-telangiectasia (A-T) patient fibroblast derived iPS cells and A-T patient fibroblasts for hybridization to the Affymetrix gene expression microarrays.
2016-03-29 | E-GEOD-78716 | biostudies-arrayexpress