RNA sequencing of a Spinocerebellar ataxia type 3 (SCA3) mouse model containing the full human ATXN3 gene with a repeat expansion of 75-80 CAGs I
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE107958 | GEO | 2017/12/13
SECONDARY ACCESSION(S): PRJNA422042
REPOSITORIES: GEO
Similar Datasets
Project description:We have performed RNA sequencing analysis of brain tissue and blood from the MJD84.2 mouse model for SCA3 (described by Cemal et al, Human molecular genetics 2002, 11:1075-1094). Blood samples were taken by tailcut at 40 and 75 weeks of age (9.2 and 17.2 months). RNA was isolated from blood, globin reduction and RNA sequencing on polyA enriched RNA were performed.
2017-12-15 | GSE108069 | GEO
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
Project description:The neurodegenerative disease spinocerebellar ataxia type 3 (SCA3; also called Machado-Joseph disease, MJD) is a trinucleotide repeat disorder caused by expansion of CAG repeats which encoding an abnormal long polyglutamine (polyQ) tract in ataxin-3 of the ATXN3 gene. Even now the pathogenic mechanism has remained elusive and no cure method is currently available. In this study, we first applied CRISPR/Cas9-mediated approach using homologous recombination to achieve one-step genetic correction in SCA3-specific induced pluripotent stem cells (iPSCs) by adjusting pathological 80 CAG repeats to normal 13 CAG repeats, without detectable off-target based on whole exon sequencing or polyacrylamide gel electrophoresis (PAGE). The correction normalized SCA3 pathogenic signal pathways (like transcription, apoptosis, and ubiquitin-dependent protein catabolic process) and reversed disease-associated phenotypes. Our strategy provides deep insights into pathogenic mechanism of SCA3 disease and suggests potential therapeutic applications of trinucleotide repeat disorders.
2020-01-17 | GSE93713 | GEO
Project description:Spinocerebellar ataxia type 3 (SCA3/MJD) has a polyQ etiology but, the current knowledge on molecular processes and proteins involved in pathogenesis is insufficient. Due to its proteolytic function, Ataxin-3 can influence other proteins, yet the global picture of crucial proteins and pathways in SCA3 was not investigated previously. Here, we explored molecular SCA3 mechanism by interdisciplinary research paradigm combining SCA3 knock-in model, behavior, MRI, brain proteomics, precise axonal proteomics, neuronal energy recordings, labeling of vesicles, and inclusions and focusing in axonal compartment. Using the global proteomics, we found dysregulation of protein homeostasis over the entire disease progression. The early SCA3 phase was associated with reduced body weight gain, the presence of the number of dysregulated proteins related to metabolism and mitochondria, and an altered profile of oxygen consumption rate in neurons. Moreover, the early phase presented alterations of protein metabolism, cytoskeletal architecture, axonal and synaptic proteins. Protein dysregulations indicated that the compartment involved in SCA3 pathogenesis next to the mitochondria are also neuronal processes and axons in particular. To confirm that the axon is one of the central compartments in SCA3 pathogenesis, we performed targeted proteomics on axons and somatodendritic compartments. We revealed highly increased axonal localization of protein synthesis machinery, including ribosomes, translation factors, and RNA binding proteins, while the level of proteins responsible for cellular transport and mitochondria was decreased. In summary, the SCA3 disease mechanism is based on the broad influence of mutant ataxin-3 on the neuronal proteome. Processes central in our SCA3 model include disturbed localization of proteins between axonal and somatodendritic compartment, early neuronal energy deficit, altered neuronal cytoskeletal structure, an overabundance of protein synthetic machinery in axons.
2021-04-08 | PXD024945 | Pride
Project description:mRNA profiles of 10-week mice in wild-type (WT), Atxn1_154Q/2Q (SCA1), Atxn1_154Q[V5591A;S602D]/2Q (154Q AXH) genotypes across 5 different brain regions (cerebellum, brainstem, hippocampus, striatum and cortex)
2022-12-13 | GSE218283 | GEO
Project description:Spinocerebellar ataxia type 3 (SCA3) is an adult-onset neurodegenerative disease caused by a polyglutamine expansion in the ataxin-3 (ATXN3) gene. No effective treatment is available for this disorder, other than symptomatic approaches. Bile acids have shown therapeutic efficacy in neurodegenerative disease models. Here, we pinpointed tauroursodeoxycholic acid (TUDCA) as an efficient therapeutic, improving the motor and neuropathological phenotype of SCA3 nematode and mouse models. Surprisingly, transcriptomic and functional in vivo data showed that TUDCA acts in neuronal tissue through the glucocorticoid receptor (GR), but independently of its canonical receptor, the FXR. TUDCA was also predicted to bind to the GR, similarly to corticosteroid molecules. GR levels were decreased in disease-affected brain regions, likely due to increased protein degradation as a consequence of ATXN3 dysfunction, being restored by TUDCA treatment. Lastly, based on results of a cohort of pre-symptomatic and symptomatic SCA3 patients, we demonstrated that peripheral expression of GR and FKBP5 might be indicators of clinical conversion and disease progression, respectively. We have established a novel in vivo mechanism for the neuroprotective effects of TUDCA in SCA3, and propose this readily available drug for a clinical trial in SCA3 patients.
2024-03-01 | GSE252250 | GEO
Project description:Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventative or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications. Consequently, therapeutic interventions often overlook non-neuronal contributions to disease. Our lab recently reported that oligodendrocytes display some of the earliest and most progressive dysfunction in SCA3 mice. Evidence of disease-associated oligodendrocyte signatures has also been reported in other neurodegenerative diseases, including Alzheimer's disease, Amyotrophic Lateral Sclerosis, Parkinson's disease, and Huntington's disease. Here, we assess the effects of anti-ATXN3 antisense oligonucleotide (ASO) treatment on oligodendrocyte dysfunction in premanifest and symptomatic SCA3 mice. We report a severe, but modifiable, deficit in oligodendrocyte maturation caused by the toxic gain-of-function of mutant ATXN3 early in SCA3 disease that is transcriptionally, biochemically, and functionally rescued with anti-ATXN3 ASO. Our results highlight the promising use of an ASO therapy across neurodegenerative diseases that requires glial targeting in addition to affected neuronal populations.
2024-03-19 | GSE261670 | GEO
Project description:Spinocerebellar ataxia type 3 (SCA3), also called Machado-Joseph disease (MJD), is a polyQ neurodegenerative disease that is still seeking cure. We used SCA-3 84Q transgenic mice as a disease model to study the therapeutic effect of insulin-like growth factor 1 (IGF-1). Transcriptomic and metabolomic profiles were established and compared between the control (15Q), disease(84Q) and treatment(84Q+IGF-1) groups using RNA-seq and metabolic network analysis. SCA3-84Q mice showed a decrease in glycolysis, lipolysis and mitochondrial oxidative phosphorylation, and an increase in apoptosis, and IGF-1 treatment reversed the alterations slightly.
2021-08-11 | GSE178367 | GEO
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.
2009-09-12 | GSE17994 | GEO
Project description:Transcriptional changes in mouse models in SCA3
| PRJNA482631 | ENA