Transcriptome analysis of Spinocerebellar Ataxia 17 Aug
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE72176 | GEO | 2015/08/19
SECONDARY ACCESSION(S): PRJNA293239
REPOSITORIES: GEO
Similar Datasets
Project description:Ataxin 1 (Atxn1) is a protein of unknown function associated with cerebellar neurodegeneration in spinocerebellar ataxia type 1 (SCA1). SCA1 is caused by an expanded polyglutamine within Atxn1 by gain-of-function mechanisms. Lack of Atxn1 in mice triggers motor deficits in the absence of neurodegeneration or apparent neuropathological abnormalities.We extracted RNA from cerebellum of 5 Atxn1-null mice and 5 WT. Cerebellar gene expression profiles at 15 weeks of age were generated usSCA1 ing Affymetrix MOE430A arrays. Identifying the molecular pathways regulated by Atxn1 can provide insights into the early molecular mechanisms underlying neuronal dysfunction.
2006-12-01 | E-MEXP-886 | biostudies-arrayexpress
Project description:Spinocerebellar ataxia type-1 is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1 protein. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are linked to neuronal death. Here, we describe a nuclear protein aggregation model of pathogenic human ataxin-1. Using an inducible Sleeping Beauty transposon system, we overexpressed ATXN1Q82 gene in human mesenchymal stem cells that are resistant to the early cytotoxic effects of the mutant protein. We characterized the structure and the protein composition of insoluble polyQ IIBs which gradually occupy the nuclei. In response to their formation, our transcriptome analysis reveals a cerebellum-specific perturbed protein interaction network, primarily affecting protein translation. Our study resolves the previously unknown architecture of insoluble polyQ IIBs and suggests that they affect the assembly and the function of the ribosome. Our inducible cell system faithfully models a human cerebellum at the end-stage of the disease.
2020-02-18 | PXD012709 | Pride
Project description:RNA-Sequencing from human post-mortem Spinocerebellar ataxia type 3 patients. This sequencing experiment was carried out to validate that the transcriptional changes of an Ataxin-3 knock-in mouse model (expressing an expansion of 304 CAG/CAAs either heterozygous or homozygous in the murine Ataxin-3 locus) represent that transcriptional changes seen in the human disease.
| EGAS00001004241 | EGA
Project description:The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is known to lead to progressive degeneration of specific neuronal populations, including cerebellar Purkinje cells (PCs), brainstem cranial nerve nuclei and inferior olive nuclei, and spinocerebellar tracts. The disease-causing protein ataxin-1 is fairly ubiquitously expressed throughout the brain and spinal cord, but most studies have primarily focused on the role of ataxin-1 in the cerebellum and brainstem. Therefore, the functions of ataxin-1 and the effects of SCA1 mutations in other brain regions including the cortex are not well known. Here, we characterized pathology in the motor cortex of a SCA1 mouse model and performed RNA sequencing in this brain region to investigate the impact of mutant ataxin-1 towards transcriptomic alterations. We identified progressive cortical pathology and significant transcriptomic changes in the motor cortex of a SCA1 mouse model. We also identified progressive, region-specific, colocalization of p62 with mutant ataxin-1 aggregates in broad brain regions, but not the cerebellum or brainstem. A cross-regional comparison of the SCA1 cortical and cerebellar transcriptomic changes identified both common and unique gene expression changes between the two regions, including shared synaptic dysfunction and region-specific kinase regulation. These findings suggest that the cortex is progressively impacted via both shared and region-specific mechanisms in SCA1.
2022-08-22 | GSE211678 | GEO
Project description:A number of human neurodegenerative diseases result from the expansion of a glutamine repeat within the disease-causing protein. Spinocerebellar ataxia type1 is one such disease, caused by expansion of a polyglutamine tract in the novel protein ataxin-1. To faithfully model SCA1 in the mouse, we generated knock-in mice carrying 154 CAG repeats in the mouse Sca1 locus. These mice reproduced many aspects of the human disease. Despite ubiquitous expression of the mutant protein, they developed slowly progressive selective neurodegeneration , which is most distinct in Purkinje cells and spinal cord. Alterations in gene expression have been proposed to be involved in the pathogenesis of polyglutamine disease including SCA1, but the changes of gene expression in an authentic disease model have not been characterized. We believe that knowledge of these genes will give insight into the pathophysiology of SCA1 and may ultimately be relevant to the treatment of SCA1.,We will determine gene expression patterns in the cerebellum and forebrain at three different time points.,We propose that the genes whose expression is affected by mutant ataxin-1 expression are effectors for neuronal dysfunction and neuronal degeneration in the knock-in mice. We also hypothesize the difference in the expression levels of these genes accounts for selective vulnerability of neurons.,We will examine three time points: 4 weeks, 11 weeks, and 20 weeks of age. We have shown that the mice developed motor incoordination as revealed by rotating rod test as early as 5 weeks of age but it was not until 10 weeks that they start showing clear neurological phenotype such as clasping. At each point, we will compare the pattern between the mutant and wild-type littermate. Animals will be prepared and sacrificed by a standard procedure. Cerebellum and spinal cord are the most affected areas whereas forebrain shows less neurodegeneration. Tissue will be rapidly dissected from cerebellum and forebrain, frozen in liquid nitrogen, and stored at ?80 C until analysis. Tissues will be sent to the centers (as opposed to RNA). We will be providing 9 tissue samples from three litters for each time point to mitigate any expression differences resulting from subtle differences of procedure or environment where the mice grow.
2007-07-07 | E-GEOD-2867 | biostudies-arrayexpress
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:Identifying common and region-specific disease signatures in Spinocerebellar Ataxia type 1 cortex and cerebellum
| PRJNA871289 | ENA
Project description:Transcriptomic approach reveals splicing dysregulation in spinocerebellar ataxia type 1
| PRJNA971864 | ENA