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Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model (miRNA-Seq)

ABSTRACT: Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model (miRNA-Seq)

PROVIDER: PRJNA1051070 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27175700.fastq.gz	Fastqsanger.gz
	SRR27175701.fastq.gz	Fastqsanger.gz
	SRR27175702.fastq.gz	Fastqsanger.gz
	SRR27175703.fastq.gz	Fastqsanger.gz
	SRR27175704.fastq.gz	Fastqsanger.gz

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Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model (miRNA-Seq)

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

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Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model (RNA-Seq)

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Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model

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.

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Examining differentially expressed genes and pathways within the striatum using a rodent model of DYT-TOR1A dystonia

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.

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Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model

Project description:Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model

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Transcriptomic profiling of DYT-TOR1A patients-derived iPSC reveals dysregulation in extracellular matrix, lipid metabolism, and Chr22q11.23

Project description:DYT-TOR1A is an early-onset generalised movement disorder characterised by involuntary muscle contractions, leading to abnormal postures and repetitive movements. The trinucleotide GAG in-frame deletion (ΔGAG) in the TOR1A gene is the most common Mendelian form of dystonia. The TOR1A gene encodes for TorsinA protein, involved in several molecular functions, including chaperone activity, protein quality control, synaptic vesicle recycling, vesicular trafficking, protein folding, homeostasis of the nuclear envelope integrity, and lipid metabolism. There is increasing evidence that DYT-TOR1A dystonia is a neurodevelopmental disorder, beginning in the period where structural and functional abnormalities manifest early in physiological maturation. Recent publications have highlighted the importance of the extracellular matrix and lipid metabolism in dystonia, processes important to cellular neurodevelopment. In is study we aimed to elucidate the gene expression profiles of mutant DYT-TOR1A patient-derived iPSCs to identify key pathways and differentially expressed proteins involved in the early stages of neurodevelopment. Our goal was to identify key molecular pathways and regulatory networks involved in early neurodevelopment that may be disrupted in the presence of the ΔGAG mutation. Through differential gene expression analysis, we sought to uncover potential alterations related to extracellular signalling, lipid homeostasis, and nuclear regulatory mechanisms. This study aims to advance our understanding of the early developmental mechanisms underpinning DYT-TOR1A dystonia and provide a foundation for further investigation into disease-specific molecular targets.

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Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model (RNA-Seq)

Project description:Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model (RNA-Seq)

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Examining differentially expressed genes and pathways within the striatum using a rodent model of DYT-TOR1A dystonia

Project description:Examining differentially expressed genes and pathways within the striatum using a rodent model of DYT-TOR1A dystonia

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A ROLE FOR DYSTONIA-ASSOCIATED GENES IN SPINAL GABAERGIC INTERNEURON CIRCUITRY

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.

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Gene-environment interaction elicits dystonia-like features and impaired translational regulation in a DYT-TOR1A mouse model

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-03-05 | GSE249877 | GEO