Molecular pathways involved in neuronal degeneration of polyglutamine mouse models
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE3634 | GEO | 2006/11/18
SECONDARY ACCESSION(S): PRJNA93749
REPOSITORIES: GEO
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Project description:To elucidate the pathways involved in the SCA7 retinal degeneration, we used DNA GeneChips and compared the gene expression profiles of the mutant mice (R7E) and the control ones (R7N). We performed these experiments at the onset stage of the disease (3w) as well as on the moderate one (9w) in order to correlate the transcriptional deregulations with the phenotype progression. We also compared the R6/2 mice vs wild type (wt) ones to identify between the deregulated transcripts the ones that were also differentially expressed in the R7E vs R7N mice. These common changes are likely caused by polyQ expansion independently of the protein context. Experiment Overall Design: Retina RNA was prepared from 4-6 animals from each mouse line. Each RNA sample was independently hybridized on a different Genehip.
2009-02-07 | E-GEOD-3634 | biostudies-arrayexpress
Project description:To determine if STAGA complex dysfunction affects chromatin remodeling in SCA7 cerebellar degeneration, we pursued unbiased ChIP-Seq analysis of histone 3 lysine 9 acetylation (H3K9ac), as this histone mark is an established indicator of open chromatin in the transcription regulatory regions of most genes. We studied SCA7 266Q knock-in mice which faithfully recapitulate a severe, rapidly progressive neurodegenerative phenotype involving the cerebellum. We detected altered H3K9ac in the promoter regions of 777 genes in the cerebellum of SCA7 266Q knock-in mice and wild-type littermate control mice, and noted that the vast majority of these chromatin alterations corresponded to markedly increased H3K9 promoter acetylation in genes expressed in the cerebellum of SCA7 model mice.
2021-02-04 | GSE166118 | GEO
Project description:Polyglutamine(polyQ) expansion of α1A voltage-dependent calcium channel (Cav2.1) is the causative mutation of spinocerebellar ataxia type 6 (SCA6). The C-terminal fragment (CTF) of Cav2.1 makes aggregates in the cytoplasm of SCA6 Purkinje cells and may relate to the pathogenesis. In order to identify genes associated with polyQ expansion and subcellular localization of CTF, we analyzed gene expression profiles of PC12 rat pheochromocytoma cells using Tet-off system.
2013-03-13 | GSE26933 | GEO
Project description:Polyglutamine(polyQ) expansion of ?1A voltage-dependent calcium channel (Cav2.1) is the causative mutation of spinocerebellar ataxia type 6 (SCA6). The C-terminal fragment (CTF) of Cav2.1 makes aggregates in the cytoplasm of SCA6 Purkinje cells and may relate to the pathogenesis. In order to identify genes associated with polyQ expansion and subcellular localization of CTF, we analyzed gene expression profiles of PC12 rat pheochromocytoma cells using Tet-off system. We exmined gene expression profiles of Tet-off PC12 cells using the following four recombinant C-terminal fragments (rCTFs): rCTF-Q13-NLS, rCTF-Q13-NES, rCTF-Q28-NLS and rCTF-Q28-NES. We obtained gene expression data of both Dox (+) and Dox (-) conditions for each CTF. All assays were performed in duplicate.
2013-03-13 | E-GEOD-26933 | biostudies-arrayexpress
Project description:Spinocerebellar ataxia type 7 (SCA7) belonging to a family of autosomal dominant cerebellar ataxias (ADCAs) is pathomechanistically associated with the group of polyglutamine expansion disorders which include SCA 1-3, 6, 7 and 17, and Huntington’s disease. These rare diseases share a common mutational feature that is the expansion of CAG repeat sequence in disease causing genes. These mutations lead to neuronal accumulation of expanded polyglutamine proteins and selective patterns of neurodegeneration. SCA7 is caused by a polyglutamine expansion in ATAXIN-7 (ATXN7), a subcomponent of co-activatory transcriptional complex SAGA and primarily affects the cerebellum, retina and brainstem. Currently, only treatments alleviating symptoms are available to patients. Allele-selective lowering of mutant polyQ proteins promises to have high therapeutic outcomes and safety profiles. In this study, PhP.eB adeno-associated virus (AAV PhP.eB) was used to deliver several shRNAs targeting expanded CAG repeats that were tested for their safety and efficacy to lower the mATXN7 level in the brain. The SCA7140Q/5Q knock-in mice that expresses a mutated Atxn7 allele harboring an expansion of 140 CAG triplet repeats and the wild type mouse allele with 5 CAGs were used in the study. Our SCA7 140Q/5Q KI mouse model remarkably recapitulates cardinal features of SCA7 and bears the potential for pre-clinical trials (Niewiadomska-Cimicka et al., J.Neurosci., 2021). We showed that systemic injection of the AAV-shA4, the most allele-selective and safe reagent of our collection, results in improvement of motor phenotypes as indicated in open field test, and partial correction of transcriptional alterations in the cerebellum of SCA7 mice.
2024-05-14 | GSE244970 | GEO
Project description:Comparative analysis of cerebellar gene expression changes occurring in Sca1154Q/2Q and Sca7266Q/5Q knock-in mice; Polyglutamine diseases are inherited neurodegenerative disorders caused by expansion of CAG repeats encoding a glutamine tract in the disease-causing proteins. There are nine disorders each having distinct features but also clinical and pathological similarities. In particular, spinocerebellar ataxia type 1 and type 7 (SCA1 and SCA7) patients manifest cerebellar ataxia with degeneration of Purkinje cells. To determine whether the disorders share molecular pathogenic events, we studied two mouse models of SCA1 and SCA7 that express the glutamine-expanded protein from the respective endogenous loci. We found common transcriptional changes, with down-regulation of Insulin-like growth factor binding protein 5 (Igfbp5) representing one of the most robust changes. Igfbp5 down-regulation occurred in granule neurons through a non-cell autonomous mechanism and was concomitant with activation of of the Insulin-like growth factor (IGF) pathway and the type I IGF receptor on Purkinje cells. These data define one common pathogenic response in SCA1 and SCA7 and reveal the importance of intercellular mechanisms in their pathogenesis. Given that SCA1 and SCA7 share a cerebellar degenerative phenotype, we proposed that some shared molecular changes might occur in both diseases, and that common molecular alterations could pinpoint pathways that could be targeted to modulate or monitor the pathogenesis of more than one disease. We focused on transcriptional changes because both ATXN1 and ATXN7 play roles in transcriptional regulation and transcriptional defects can be detected in early-symptomatic stages of both SCA1 and SCA7 mouse models. To test our hypothesis, we examined cerebellar gene expression patterns in SCA1 and SCA7 knock-in (KI) models--Sca1154Q/2Q and Sca7266Q/5Q mice. Experiment Overall Design: Total cerebellar RNA samples were collected from Sca1154Q/2Q knock-in and wild type mice at the early symptomatic disease stage (4 weeks, n=3 knock-in and 3 wild type; 9-12 weeks, n=3 knock-in and 3 wild type). In parallel experiments, total cerebellar RNA samples were collected from Sca7266Q/5Q knock-in and wild type mice also at the early symptomatic disease stage (5 weeks, n=5 knock-in and 5 wild type).
2009-01-09 | E-GEOD-9914 | biostudies-arrayexpress
Project description:Spinocerebellar Ataxia Type 7 (SCA7) belonging to ADCAs is pathomechanistically related to a group of polyglutamine expansion disorders. SCA7 affects primarily brainstem, retina and cerebellum. The distinctive feature of SCA7 among ADCAs is a progressive visual impairment due to a cone-rod photoreceptor dystrophy. Ultrastructural analysis of SCA7 mouse models revealed that photoreceptors progressively lose their outer segments, a structure essential for phototransduction, which requires daily renewal. The lack of outer segment renewal correlates with decreased expression of photoreceptor-specific genes, suggesting that progressive breakdown of photoreceptor cell identity accounts for SCA7 retinopathy. SCA7 is due to a polyglutamine expansion in ATXN7, a component of the multiprotein SPT-ADA-GCN5 Acetyltransferase (SAGA) complex, a highly conserved coactivator of transcription. SAGA harbors two chromatin remodeling activities: acetylation and deubiquitynation of histones crucial for transcription initiation and elongation. The role of SAGA in SCA7 pathogenesis and the tissue specific genetic breakdown remains to be elucidated. We addressed this issue using our new SCA7 knock-in mouse model (SCA7140Q/140Q), which recapitulates cardinal features of SCA7. Using ChIP-seq approach, we confirmed the general decrease of H3K9ac in most gene promoters in SCA7 retina, which alone cannot explain the specific gene deregulation. Interestingly, we discovered that photoreceptor identity genes, which are strongly downregulated in SCA7, harbor an unusual broad profile of H3K9ac that encompasses the entire gene. We further show that H3K9ac broad profiles at photoreceptor gene loci coincide with the presence of a broad H3K27ac, a signature of superenhancers. Furthermore, using vicinity criteria we identified enhancer RNAs (eRNAs), annotated to the photoreceptor identity genes possessing an atypical H3K9ac/H3K27ac enhancer signature. Finally, we found a synchronized expression of eRNAs and photoreceptor identity genes during retinal development, suggesting a regulatory role of these eRNAs. The decreased eRNA levels on hypoacetylated loci in the retina correlate with the downregulation of photoreceptor identity genes in symptomatic but not in pre-symptomatic SCA7 mice. Our results support the view that epigenetic and enhancer alterations compromise the maintenance of neuronal identity in SCA7.
2022-12-20 | GSE181323 | GEO
Project description:Spinocerebellar Ataxia Type 7 (SCA7) belonging to ADCAs is pathomechanistically related to a group of polyglutamine expansion disorders. SCA7 affects primarily brainstem, retina and cerebellum. The distinctive feature of SCA7 among ADCAs is a progressive visual impairment due to a cone-rod photoreceptor dystrophy. Ultrastructural analysis of SCA7 mouse models revealed that photoreceptors progressively lose their outer segments, a structure essential for phototransduction, which requires daily renewal. The lack of outer segment renewal correlates with decreased expression of photoreceptor-specific genes, suggesting that progressive breakdown of photoreceptor cell identity accounts for SCA7 retinopathy. SCA7 is due to a polyglutamine expansion in ATXN7, a component of the multiprotein SPT-ADA-GCN5 Acetyltransferase (SAGA) complex, a highly conserved coactivator of transcription. SAGA harbors two chromatin remodeling activities: acetylation and deubiquitynation of histones crucial for transcription initiation and elongation. The role of SAGA in SCA7 pathogenesis and the tissue specific genetic breakdown remains to be elucidated. We addressed this issue using our new SCA7 knock-in mouse model (SCA7140Q/140Q), which recapitulates cardinal features of SCA7. Using ChIP-seq approach, we confirmed the general decrease of H3K9ac in most gene promoters in SCA7 retina, which alone cannot explain the specific gene deregulation. Interestingly, we discovered that photoreceptor identity genes, which are strongly downregulated in SCA7, harbor an unusual broad profile of H3K9ac that encompasses the entire gene. We further show that H3K9ac broad profiles at photoreceptor gene loci coincide with the presence of a broad H3K27ac, a signature of superenhancers. Furthermore, using vicinity criteria we identified enhancer RNAs (eRNAs), annotated to the photoreceptor identity genes possessing an atypical H3K9ac/H3K27ac enhancer signature. Finally, we found a synchronized expression of eRNAs and photoreceptor identity genes during retinal development, suggesting a regulatory role of these eRNAs. The decreased eRNA levels on hypoacetylated loci in the retina correlate with the downregulation of photoreceptor identity genes in symptomatic but not in pre-symptomatic SCA7 mice.
2022-12-20 | GSE181324 | GEO
Project description:Huntington’s disease is a monogenic disorder, with only one known causative gene, huntingtin (HTT). Expansion of a trinucleotide (CAG) repeat within the HTT gene results in a mutant protein containing polyglutamine (polyQ) stretches. While mutant HTT is the primary driver of cellular degeneration in the brain, the molecular and cellular mechanisms are incompletely understood. To further understand the role of polyQ in disease pathogenesis, we studied the dynamics of HTT protein-protein interactions (PPIs) in the striatum of mice with wild-type (Q20) and mutant (Q140) HTT at pre-symptomatic and manifest HD ages using label-free and isotope-labeled IP-MS approaches. Combining these approaches, we demonstrated that HTT PPI dynamics are distinct in early and later disease phases. Computational analysis pointed to early protein interaction changes involving synaptic transmission and vesicle fusion functions, while later interactions underlie changes in synapse morphogenesis and impact the actin cytoskeletal network.
2022-02-20 | PXD025510 | Pride
Project description:Dentatorubral-pallidoluysian Atrophy (DRPLA) is a human polyQ disease caused by the expansion of a CAG strech in the atrophin-1 (at-1) gene. In all vertebrates, a second atrophin gene (at-2) is present and it encodes a related protein void of polyQ tracks. In D.melanogaster there is one conserved Atrophin (Atro) gene, ubiquitously expressed, which contains all functional domains of vertebrate Atrophins, including two polyQ stretches. To understand to what extent transcriptional alterations cause neurodegeneration and are linked to the normal functions of Atrophin, we performed a genome wide transcriptional profiling in our Drosophila models, focusing on primary events that precede neurodegeneration. We have found that polyQ Atro downregulates fat, which protects from neurodegeneration and Atrophin toxicity trhough the Hippo kinase cascade.
2011-03-01 | GSE26246 | GEO