Dysregulation of zebrin-II cell subtypes in the cerebellum is a shared feature across polyglutamine ataxia mouse models and patients
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE269430 | GEO | 2024/08/14
REPOSITORIES: GEO
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Project description:Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination due to progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-3, 6 and 17, however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7140Q/5Q, we analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphological alterations, pacemaker dysfunction and motor incoordination. Strikingly, most PC genes downregulated in SCA7 have also decreased expression in SCA1 and SCA2 mice, revealing converging pathomechanisms and a common disease signature involving cGMP-PKG and phosphatidylinositol signaling pathways and long-term depression. Our study thus points out molecular targets for therapeutic development, which may prove beneficial for several SCAs. Furthermore, we show that SCA7140Q/5Q males and females exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology and photoreceptor dystrophy, which account for progressive impairment of behavior, motor and visual functions. SCA7140Q/5Q mice represent an accurate model for the investigation of different aspects of SCA7.
2021-04-26 | GSE138527 | GEO
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: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:Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, the causal link between the activation of microglia in the cerebellum and ataxias remains inconclusive. In the present study, using a classic mouse model of cerebellar ataxia induced by 3-acetylpyridine (3-AP), we find a early-onset and long-lasting microglial activation accompanied by neuronal loss and dysfunction in the cerebellum. Transcriptome and behavior analyses indicate that microglial depletion in 3-AP ataxic mice decreases neuroinflammatory response in the cerebellum and rescues the ataxic motor symptoms including motor incoordination, gait abnormality, and locomotor dysfunction. Moreover, specific chemogenetic activation of cerebellar microglia in the vermis by M3D(Gq), a designer receptor exclusively activated by designer drugs (DREADDs), directly induces an expression of pro-inflammatory cytokines and aggravates ataxic motor deficits of 3-AP mice. On the contrary, inhibition of cerebellar microglial activation by M4D(Gi) or minocycline reduces the production of pro-inflammatory cytokines including TNF-α and alleviates motor deficits. Furthermore, blockage of TNF-α signaling attenuates the microglial-triggered hyperactivity of Purkinje cells (PCs). These results suggest that cerebellar microglial activation aggravates neuroinflammatory response, and subsequently induces dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between pro-inflammatory activation of cerebellar microglia and the ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.
2023-07-01 | GSE221991 | 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: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. Keywords: comparative disesae state analysis between Sca1154Q/2Q and Sca7266Q/5Q knock-in cerebellum
2007-12-18 | GSE9914 | GEO
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. Keywords: Polyglutamine disorders, Spinocerebellar ataxia type 7 (SCA7), Huntington’s disease (HD), Neuronal dysfunction, Retinal degeneration
2006-11-18 | GSE3634 | GEO
Project description:Background Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder that primarily affects the cerebellum and retina. SCA7 is caused by a polyglutamine expansion in the ATXN7 protein, a subunit of the transcriptional coactivator SAGA that acetylates histone H3 to deposit narrow H3K9ac mark at DNA regulatory elements of active genes. Defective histone acetylation has been presented as a possible cause for gene deregulation in SCA7 mouse models. However, the topography of acetylation defects at the whole genome level and its relationship to changes in gene expression remain to be determined. Methods We performed deep RNA-sequencing and chromatin immunoprecipitation coupled to high-throughput sequencing to examine the genome-wide correlation between gene deregulation and alteration of the active transcription marks, e.g. SAGA-related H3K9ac, CBP-related H3K27ac and RNA polymerase II (RNAPII), in a SCA7 mouse retinopathy model. Results Our analyses revealed that active transcription marks are reduced at most gene promoters in SCA7 retina, while a limited number of genes show changes in expression. We found that SCA7 retinopathy is caused by preferential downregulation of hundreds of highly expressed genes that define morphological and physiological identities of mature photoreceptors. We further uncovered that these photoreceptor genes harbor unusually broad H3K9ac profiles spanning the entire gene bodies and have a low RNAPII pausing. This broad H3K9ac signature co-occurs with other features that delineate superenhancers, including broad H3K27ac, binding sites for photoreceptor specific transcription factors and expression of enhancer-related non-coding RNAs (eRNAs). In SCA7 retina, downregulated photoreceptor genes show decreased H3K9 and H3K27 acetylation and eRNA expression as well as increased RNAPII pausing, suggesting that superenhancer-related features are altered. Conclusions Our study thus provides evidence that distinctive epigenetic configurations underlying high expression of cell-type specific genes are preferentially impaired in SCA7, resulting in a defect in the maintenance of identity features of mature photoreceptors. Our results also suggest that continuous SAGA-driven acetylation plays a role in preserving post-mitotic neuronal identity.
2022-12-20 | GSE181325 | 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: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