Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1219152 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32229300_1.fastq.gz | Fastqsanger.gz | |||
| SRR32229300_2.fastq.gz | Fastqsanger.gz | |||
| SRR32229301_1.fastq.gz | Fastqsanger.gz | |||
| SRR32229301_2.fastq.gz | Fastqsanger.gz | |||
| SRR32229302_1.fastq.gz | Fastqsanger.gz |
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Project description:Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent muscle contraction and abnormal postures. Several dystonia-associated mutations have been identified. The common theme across the majority of studies utilizing animal models that recapitulate these mutations have indicated mechanisms of sustained, imperturbable long-term potentiation of corticostriatal synapses in medium spiny neurons (MSNs) and reduced ability to induce long-term depression. This suggests a striato-centric neuronal adaptive response to mutation that may drive disease pathology. However, the cell type-specificity and molecular programs driving these changes are unknown. To address this, we utilized single-nucleus RNA-sequencing on striatal cells extracted from two dystonia mouse models that recapitulate genetic mutations linked to dystonia: DYT1 (Tor1awt/ E) and DYT25 (Gnal+/-). Upon analysis, MSNs exhibited the majority of transcriptional changes: Gnal deficiency was associated with downregulation of genes involved in the maintenance of membrane potential and increased expression of those encoding for neuron development-related molecules. Mice with Tor1awt/ E mutation had enhanced expression of specific immediate early genes (Arc and Npas4) in MSNs. These alterations may drive and/or reflect the altered plasticity mechanisms observed in dystonia. Changes in transcription of several genes in MSNs were shared across both mouse models, including Lrrk2, Reln, and Pkrcb. Further exploration of these and other shared pathways may open new avenues for future investigation of strategies to treat dystonia and other conditions related to GNAL or TOR1A dysfunction.
2026-08-31 | GSE345347 | GEO
Project description:Introduction Pathogenic variants in KMT2B cause early-onset dystonia, but a mouse model that has undergone comprehensive, dystonia-oriented phenotyping is lacking. Methods We conducted detailed phenotyping on heterozygous Kmt2b constitutive knockout mice and wild-type littermates, assessing growth, neurobehavioral traits, motor coordination, sensorimotor gating, social behavior and metabolic parameters, combined with striatal RNA sequencing. Results Kmt2b knockout mice of both sexes were viable but significantly smaller and lighter than littermate controls. Knockouts were hyperlocomotive in the open field and showed approximately two-fold larger acoustic startle responses; unexpectedly, prepulse inhibition was enhanced rather than reduced at all prepulse intensities. On the balance beam, knockouts crossed more slowly and paused more frequently; female knockouts also paused more on the ladder rung task. Frame-by-frame video analysis revealed a claw-like hindpaw posture characterized by abnormal inward flexion of the digits. Knockout mice spent less time investigating a novel conspecific, while social recognition memory remained intact. Striatal RNA sequencing confirmed reduction of Kmt2b transcript to approximately half of control levels and identified 177 differentially expressed genes, including Maob, encoding monoamine oxidase B; gene set enrichment analysis implicated neurodevelopmental, glial and mitochondrial processes. Nociception, vision, body-weight-adjusted grip strength, and clinical chemistry and hematological measures were largely unaffected. Conclusion Heterozygous Kmt2b knockout mice show hyperlocomotion, altered sensorimotor gating, impaired motor coordination with dystonic-like paw posturing and reduced sociability, alongside a striatal transcriptomic signature implicating neurodevelopmental processes. The model mirrors aspects of human KMT2B-related dystonia and provides a platform for mechanistic study; environmental or pharmacological challenge may be needed to unmask overt dystonic features.
2026-09-10 | GSE346547 | GEO
Project description:Dysregulation of the striatum is linked to multiple diseases including Huntington’s (HD), Parkinson’s, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neuronal cell type in the striatum and are critical to motor control. The transcription factor Bcl11b (also known as CTIP2) is known to regulate of MSN differentiation, striatal striosome (patch) development and the architecture of the striatum during development. However, the function of Bcl11b adult striatal neurons in vivo has not been investigated. Therefore, we conditionally knocked out Bcl11b specifically in MSNs using D9-cre under the control of a regulatory elements of the mouse Ppp1r1b gene encoding DARPP-32 resulting in knockout around 5-6 weeks of age. Transcriptomic and behavioral analysis were performed on these mice.
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Project description:The molecular mechanisms that underlie striatal subregional and cell subtype-specific vulnerabilities and the cascade of molecular events occurring during Huntington’s disease remain poorly defined. ATAC libraries from early-grade Huntington’s disease striatum across two striatal subregions were generated and then HTT molecules were enriched by hybridization and sequencing following long-read sequencing preparation to predict HTT CAG repeat lengths corresponding to nuclei barcodes. These data identify MSNs as the predominant cell type undergoing HTT CAG repeat expansion, characterize subregional and cell type-differences in repeat expansion, and explore the relationship between MSN de-repression and repeat expansion.
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Project description:The molecular mechanisms that underlie striatal development and organization remain largely unknown. Here, we show that Foxp1, a transcription factor strongly linked to autism and intellectual disability, regulates organizational features of striatal circuitry in a cell-type dependent fashion. Using single-cell RNA-sequencing, we examine the cellular diversity of the early postnatal striatum and demonstrate that Foxp1 specifies a subpopulation of indirect pathway spiny projection neurons (iSPNs) while maintaining the striosome-matrix architecture through molecular mechanisms mediated by direct pathway spiny projection neurons (dSPNs). Functionally, Foxp1 alters striatal projection patterns both cell-autonomously and non-autonomously. We connect these changes in striatal circuitry to distinct behavioral deficits relevant to phenotypes described in patients with FOXP1 loss-of-function mutations. These data reveal novel cell-type specific transcriptional mechanisms underlying distinct features of striatal circuitry and identify Foxp1 as a key regulator of striatal development
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Project description:Selective degeneration of striatal projection neurons is one of the main features of Huntington’s disease (HD). The differences between vulnerable and resilient striatal cell types and cell type-specific molecular events associated with HD progression have not been established. Here we employed fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of different cell types of the human striatum in HD and control donors.
2023-12-04 | GSE227729 | GEO
Project description:THAP1 is a transcription factor and its mutations are responsible for DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems to uncover the function of THAP1 and the potential pathogenesis of DYT6 dystonia. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner.
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Project description:A molecular calcium integrator reveals a striatal cell-type driving aversion
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Project description:To elicit a dystonia-like phenotype in a genetically predisposed DYT-TOR1A mouse model (DYT1KI) by performing a right sciatic nerve crush injury. To identify novel pathophysiological pathways and possible biomarker, we performed a multi-omic analysis of three dystonia-relevant brain regions
2024-03-05 | GSE249876 | GEO
Project description:Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (Htt) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4,524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, HttQ175/+, and from wildtype controls. We used 14-15-month-old mice, a time point roughly equivalent to an early stage of symptomatic human disease. Cell count distributions indicated selective loss of D2 MSNs and increased microglia in aged HttQ175/+ mice. Thousands of differentially expressed genes were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the Polycomb Repressive Complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum.
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