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Transcriptomic approach reveals splicing dysregulation in spinocerebellar ataxia type 1

ABSTRACT: Transcriptomic approach reveals splicing dysregulation in spinocerebellar ataxia type 1

PROVIDER: PRJNA971864 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24519958_1.fastq.gz	Fastqsanger.gz
	SRR24519958_2.fastq.gz	Fastqsanger.gz
	SRR24519959_1.fastq.gz	Fastqsanger.gz
	SRR24519959_2.fastq.gz	Fastqsanger.gz
	SRR24519960_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Transcriptomic approach reveals splicing dysregulation in spinocerebellar ataxia type 1

Project description:Spinocerebellar ataxia type 1 (SCA1) is caused by a polyglutamine expansion in the ATXN1 gene leading to an expanded polyglutamine tract in the ATAXIN-1 protein. Ataxin-1 is broadly expressed throughout the brain and is known to be involved in regulating gene expression; however, it is not yet determined if mutant ataxin-1 regulates alternative splicing events. Utilizing SCA1 mouse models, we performed bulk RNA sequencing and looked for misregulated alternative splicing (mAS) events in SCA1 mouse cerebella. We found that mutant ataxin-1 causes mAS events to occur in the SCA1 mouse cerebella. Furthermore, we showed that abnormal splicing events predominantly occur in cell types that express mutant ataxin-1. Less than 25% of the mAS events were also differentially expressed genes (DEGs) and therefore their transcriptional dysregulation was previously unknown in the context of SCA1. We show through gene ontology analysis that mAS events reveal new biological pathways: mAS events showed changes in structural morphogenesis whereas DEGs showed changes in ion channel and transmembrane transport. We also report that mutant ataxin-1 causes dysregulation of expression of other ataxia-causing genes, providing evidence for molecular basis of clinical similarity among otherwise heterogeneous inherited cerebellar ataxias. We also identified the potential mechanism by which mutant ATXN1 causes mAS through its interaction with RBFOX1.

2023-10-20 | GSE232368 | 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

MicroRNA dysregulation in Ataxia Telangiectasia

Project description:MicroRNA dysregulation in Ataxia Telangiectasia

| PRJNA1107187 | ENA

Epigenetic dysregulation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7

Project description:Epigenetic dysregulation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7

| PRJNA699293 | ENA

Dysregulation of alternative splicing in spinocerebellar ataxia type 1.

Project description:Spinocerebellar ataxia type 1 is caused by an expansion of the polyglutamine tract in ATAXIN-1. Ataxin-1 is broadly expressed throughout the brain and is involved in regulating gene expression. However, it is not yet known if mutant ataxin-1 can impact the regulation of alternative splicing events. We performed RNA sequencing in mouse models of spinocerebellar ataxia type 1 and identified that mutant ataxin-1 expression abnormally leads to diverse splicing events in the mouse cerebellum of spinocerebellar ataxia type 1. We found that the diverse splicing events occurred in a predominantly cell autonomous manner. A majority of the transcripts with misregulated alternative splicing events were previously unknown, thus allowing us to identify overall new biological pathways that are distinctive to those affected by differential gene expression in spinocerebellar ataxia type 1. We also provide evidence that the splicing factor Rbfox1 mediates the effect of mutant ataxin-1 on misregulated alternative splicing and that genetic manipulation of Rbfox1 expression modifies neurodegenerative phenotypes in a Drosophila model of spinocerebellar ataxia type 1 in vivo. Together, this study provides novel molecular mechanistic insight into the pathogenesis of spinocerebellar ataxia type 1 and identifies potential therapeutic strategies for spinocerebellar ataxia type 1.

| S-EPMC10979408 | biostudies-literature

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

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

Transcription profiling of mouse spinocerebellar ataxia type 3 (SCA3) transgenic and wild type animals treated with CCI-779 or placebo

Project description:Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the expansion of the polyglutamine repeat region within the ataxin-3 protein. The mutant protein forms intracellular aggregates in the brain. However, the cellular mechanisms causing toxicity are still poorly understood and there are currently no effective treatments. In this study we show that administration of a rapamycin ester, CCI-779, improves motor performance in a transgenic mouse model of SCA3. CCI-779 inhibits mammalian target of rapamycin (mTOR) and hence upregulates protein degradation by autophagy. CCI-779 reduces the number of aggregates seen in the brains of transgenic mice and decreases levels of cytosolic soluble mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. CCI-779 is designed for long-term use in patients and therefore represents a possible therapeutic strategy for the treatment of SCA3. Using this disease model and treatment paradigm we employed a microarray approach to investigate transcriptional changes that might be important in the pathogenesis of SCA3. This approach identified Usp15, which showed expression changes at both the mRNA and protein level. Usp15 levels were also changed in mice expressing another mutant polyglutamine protein, huntingtin. In total we identified 16 transcripts that were decreased in transgenic ataxin-3 mice that were normalised following CCI-779 treatment, as the number of transcripts changed was low and the magnitude of these changes was small we suggest that transcriptional dysregulation may not be an important step in the primary pathogenesis of SCA3. Experiment Overall Design: We analyzed 19 brain samples in total. 4 samples from wt animals after placebo treatment. 5 samples from wt animals after CCI-779 treatment. 5 samples from SCA3 tg animals after placebo treatment. 5 samples from SCA3 tg animals after CCI-779 treatment.

2009-09-18 | E-GEOD-17994 | biostudies-arrayexpress

Spinocerebellar ataxia type 3 RNA-sequencing study

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

Resilience to Endoplasmic Reticulum Stress Mitigates Calcium-Dependent Membrane Hyperexcitability Underlying Late Disease Onset in Spinocerebellar Ataxia Type 6

Project description:An enduring puzzle in many inherited neurological disorders is the late onset of symptoms despite expression of function-impairing mutant protein early in life. We examined the basis for onset of impairment in Spinocerebellar ataxia type 6 (SCA6), a polyglutamine ataxia with late-onset cerebellar neurodegeneration. In a mouse model of SCA6, we identified a homeostatic response that engages the unfolded protein response early in disease. This protective response provided insight into endoplasmic reticulum (ER) stress-mediated cerebellar Purkinje neuron membrane hyperexcitability as a driver of disease. Age-dependent impairment of chaperone-mediated compensation for ER stress increased calcium-dependent Purkinje neuron membrane excitability. Redundant pathways of the unfolded protein response mediate this resilience to ER stress. ER stress-related decompensation applies also to other late-onset human cerebellar ataxia. These studies elucidate a mechanism of resilience connecting aberrant proteostasis and calcium-dependent intrinsic membrane hyperexcitability to explain delayed disease onset more widely in age-dependent neurodegenerative disease.

2025-09-24 | GSE264100 | GEO

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