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Identifying common and region-specific disease signatures in Spinocerebellar Ataxia type 1 cortex and cerebellum

ABSTRACT: Identifying common and region-specific disease signatures in Spinocerebellar Ataxia type 1 cortex and cerebellum

PROVIDER: PRJNA871289 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR21145585_1.fastq.gz	Fastqsanger.gz
	SRR21145585_2.fastq.gz	Fastqsanger.gz
	SRR21145586_1.fastq.gz	Fastqsanger.gz
	SRR21145586_2.fastq.gz	Fastqsanger.gz
	SRR21145587_1.fastq.gz	Fastqsanger.gz

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Identifying common and region-specific disease signatures in Spinocerebellar Ataxia type 1 cortex and cerebellum

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

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

Transcription profiling of ataxin-null (Atxn-null) vs. wild type mice to investigate spinocerebellar ataxia type 1 (SCA1)

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

PolyQ-expanded ataxin-1 formed insoluble protein inclusions perturbing translation in a spinocerebellar ataxia type-1 model

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

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 [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

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

Transcriptomic approach reveals splicing dysregulation in spinocerebellar ataxia type 1

Project description:Transcriptomic approach reveals splicing dysregulation in spinocerebellar ataxia type 1

| PRJNA971864 | ENA

Dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across polyglutamine ataxia mouse models and patients

Project description:Spinocerebellar ataxia type 7 (SCA7) is a genetic neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. Purkinje cells (PCs) are central to the pathology of ataxias, but their low abundance in the cerebellum underrepresents their transcriptomes in sequencing assays. To address this issue, we developed a PC enrichment protocol and sequenced individual nuclei from mice and patients with SCA7. Single-nucleus RNA sequencing in SCA7-266Q mice revealed dysregulation of cell identity genes affecting glia and PCs. Specifically, genes marking zebrin-II PC subtypes accounted for the highest proportion of DEGs in symptomatic SCA7-266Q mice. These transcriptomic changes in SCA7-266Q mice were associated with increased numbers of inhibitory synapses as quantified by immunohistochemistry and reduced spiking of PCs in acute brain slices. Dysregulation of zebrin-II cell subtypes was the predominant signal in PCs of SCA7-266Q mice and was associated with the loss of zebrin-II striping in the cerebellum at motor symptom onset. We furthermore demonstrated zebrin-II stripe degradation in additional mouse models of polyglutamine ataxia and observed decreased zebrin-II expression in the cerebella of patients with SCA7. Our results suggest that a breakdown of zebrin subtype regulation is a shared pathological feature of polyglutamine ataxias.

2024-08-14 | GSE269430 | GEO

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

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