Examining differentially expressed genes and pathways within the striatum using a rodent model of DYT-TOR1A dystonia
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PROVIDER: PRJNA1051580 | ENA |
REPOSITORIES: ENA
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Project description:DYT-TOR1A (DYT1) is the most common monogenetic form of dystonia characterized by a reduced disease penetrance of 30-40% only. Environmental factors are suspected to play a major role in eliciting dystonia in DYT1 gene carriers. In line with this observation a sciatic nerve crush injury as a traumatic environmental stimulus was previously shown to induce dystonia-like movements (DLM) in the asymptomatic DYT-TOR1A rat model (∆ETorA). The primary objective of this study was to assess the underlying pathophysiological mechanisms associated with DYT1 dystonia using this “second hit” DYT1 rodent model. The striatum, as one of the pathophysiologic key structures of dystonia, was analysed twelve weeks after nerve injury by unbiased RNA-sequencing in order to identify differentially expressed genes (DEG) and pathways.
2024-12-31 | GSE249994 | GEO
Project description:DYT-TOR1A dystonia is a movement disorder characterized by involuntary muscle contractions. Despite being the most common monogenetic form of dystonia, its pathophysiolofy remains unclear. With a reduced penetrance of about 30%, there is a suggestion that extragenetic factors are needed to develeop a dystonic phenotype. In the present study, we induced a sciatic nerve crush injury in a genetically predisposed DYT-TOR1A mouse model (DYT1KI) to evoke a dystonic phenotype. Subsequently, we employed a multi-omic approach to uncover novel pathophysiological pathways associated with DYT-TOR1A dystonia. Utilizing a deep-learning-based characterization of the dystonic phenotype, we observed that nerve-injured DYT1KI animals exhibited significantly more dystonia-like movement (DLM) compared to naive DYT1KI animals, with noticeable effects as early as two weeks post-surgery. Moreover, nerve-injured DT1KI mice displayed significantly more DLM than their wildtype (wt) counterparts starting 6 weeks post-injury. In the cerebellum of nerve-injured wt mice, multi-omice analysis indicated regulatory changes in translation-related processes, a phenomenon not observed in the cerebellum of nerve-injured DYT1KI mice; instead, these changes were localized to the cortex and striatum. Our findings suggest a failure of translational compensatory mechanisms in the cerebellum of phenotypic DY1KI mice displaying DLM, while dysregulations in translation in the cortex and striatum likely contribute to the promotion of the dystonic phenotype.
2024-03-05 | PXD047531 | Pride
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 | GSE249875 | GEO
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:Spinal interneurons are critical modulators of locomotor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. While deficits in presynaptic inhibition have been inferred in human locomotor diseases, including dystonia, it remains unknown whether GABApre circuit components are altered in these conditions. In this study, we use developmental timing to show that GABApre neurons are a late Ptf1a-expressing subclass and localize to the intermediate spinal cord. Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia related protein Tor1a. Furthermore, in Tor1a mutant mice in which Klhl14 and Tor1a binding is disrupted (Dyt1ΔE), GABApre-sensory afferent synapse formation is impaired. Our findings suggest a potential contribution of GABApre neurons to the deficits in presynaptic inhibition observed in dystonia.
2017-06-03 | GSE99590 | GEO
Project description:DYT1 dystonia is a neurological movement disorder characterized by a dominant 3-base pair deletion (dGAG) in the TOR1A gene. This study demonstrates a gene editing approach that selectively targets the dGAG mutation in the TOR1A DYT1 allele while safeguarding the wild-type (WT) TOR1A allele. We optimized an adeno-associated virus (AAV) vector-compatible variant of the Staphylococcus aureus Cas9 nuclease ortholog (SaCas9-KKH) in DYT1 patient-derived human neuroprecursor cells (hNPCs). On-target editing of the TOR1A DYT1 allele was confirmed at the genomic level from brain tissue in a xenograft mouse model. To avoid brain biopsy for demonstrating TOR1A DYT1 editing, we developed a non-invasive monitoring method using extracellular RNA (exRNA). TOR1A exRNA was retrieved from the EV secretions of hNPCs and plasma samples, indicating whether the donor was a TOR1A DYT1 carrier. This technique enabled us to assess AAV-mediated disruption of the TOR1A DYT1 allele in the brains of mice using blood samples
2025-03-01 | GSE288087 | GEO
Project description:DYT1 dystonia is an autosomal-dominantly inherited movement disorder, which is usually caused by a GAG deletion in the TOR1A gene. Due to the reduced penetrance of ~30-40%, the determination of the mutation in a subject is of limited use with regard to actual manifestation of symptoms. In the present study, we used Affymetrix oligonucleotide microarrays to analyze global gene expression in blood samples of 15 manifesting and 15 non-manifesting mutation carriers in order to identify a susceptibility profile beyond the GAG deletion which is associated with the manifestation of symptoms in DYT1 dystonia.We identified a genetic signature which distinguished between asymptomatic mutation carriers and symptomatic DYT1 patients with 86.7% sensitivity and 100% specificity. This genetic signature could correctly predict the disease state in an independent test set with a sensitivity of 87.5% and a specificity of 85.7%.Conclusively, this genetic signature might provide a possibility to distinguish DYT1 patients from asymptomatic mutation carriers. Comparison of whole blood expression profiles of patients with DYT1 dystonia with non manifesting mutation carriers and non mutation carriers
2010-05-26 | E-GEOD-19419 | biostudies-arrayexpress
Project description:DYT-THAP1 dystonia is a monogenetic form of dystonia, a movement disorder characterized by involuntary muscle contractions. The disease is caused by mutations in the THAP1 gene, although the exact mechanisms through which these mutations contribute to dystonia's pathophysiology remain elusive. The incomplete penetrance of DYT-tHAP1 dystonia, estimated between 40-60%, indicated that an environmental trigger might be necessary for the disease to manifest in genetically predisposed individuals. To explore the gene-environment interaction in dystonia development, we performed a sciatic nerve crush injury in a genetically predisposed DYTHAP1 heterozygous knockout mouse mode (Thap1+/-). Using a multi-omic approach, we investigated the underlying pathophysiological pathways. Phenotypic analysis with an unbiased deep learning algorithm showed that nerve-injured Thap1+/- mice exhibited more dystonia-like movements over the 12-week experiment than naive Thap1+/- mice. Multi-omic analysis of the cerebellum, striatum, and cortex in nerve-injured Thap1+/- mice revealed altered energy metabolism compared to naive Thap1+/- and nerve-injured wildtype mice. These findings suggest that abnormal energy metabolism in the cerebellum, striatum, and cortex may contribute to the dystonic features observed in nerve-injured Thap1+/- mice.
2025-01-03 | PXD055364 | Pride
Project description:Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model
| PRJNA1051065 | ENA
Project description:Dystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse and it is unknown whether their pathogenesis converges on shared pathways. Mutations in THAP1, a zinc-finger transcription factor, cause DYT6, but its neuronal targets and functions are unknown. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1C54Y or Exon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic Long Term Depression pathways, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays confirmed the functional significance of those findings. Notably, several of these pathways were recently implicated in other forms of inherited dystonia, including DYT1. We conclude that dysfunction of these pathways may represent a point of convergence on the pathogenesis of unrelated forms of inherited dystonia.
2017-11-11 | GSE98839 | GEO