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

ABSTRACT: 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

ORGANISM(S): Mus musculus

PROVIDER: GSE249876 | GEO | 2024/03/05

REPOSITORIES: GEO

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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: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

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

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Blood expression profiles define penetrance in DYT1 dystonia patients

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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

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EE1A1 Interactome

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