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
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ABSTRACT:
PROVIDER: PRJNA422042 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6367700_1.fastq.gz | Fastqsanger.gz | |||
| SRR6367700_2.fastq.gz | Fastqsanger.gz | |||
| SRR6367710_1.fastq.gz | Fastqsanger.gz | |||
| SRR6367710_2.fastq.gz | Fastqsanger.gz | |||
| SRR6367720_1.fastq.gz | Fastqsanger.gz |
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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: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 II
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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). Mice were 17.5 months of age at sacrifice and brainstem, cerebellum, cortex and striatum were sequenced. Transgenic SCA3 mice showed most transcriptional changes in striatum and brainstem. Axon guidance, synaptic transmission, pi-3k cascade and cholesterol biosynthesis pathways are implicated to be affected based on the transcriptional changes.
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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.
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Project description:Transcriptome analysis of extracted total RNA from the the cerebellum and muscle of Spinocerebellar Ataxia 17 knock-in mouse model
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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.
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Project description:Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide and caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyQ expansion in the corresponding protein. The disease is characterized by neuropathological (aggregate formation, cell loss), phenotypical (gait instability, body weight reduction) and transcriptional changes. So far there is no mouse model available representing all the different aspects of the disease, but a representative model is highly needed to gain a better understanding of the disease pathomechanism. Here we characterized a novel Ataxin-3 knock-in mouse model, expressing an expansion of 304 CAG/CAAs either heterozygous or homozygous in the murine Ataxin-3 locus using biochemical, behavioral and transcriptomic approaches. Further, we correlated the transcriptional changes of the knock-in mice to those found in human SCA3 patients, to prove the comparability of our model. The novel Ataxin-3 knock-in mouse is characterized by the expression of polyQ-expanded Ataxin-3 in the murine protein, leading to massive aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Caused by these neuropathological changes, the mice demonstrated phenotypically reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed downregulation of differentially expressed genes enriched in myelinating oligodendrocytes. Comparing these transcriptional changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards disturbances in the myelin sheaths and myelinating oligodendrocytes.
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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 (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