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Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice

ABSTRACT: Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice

PROVIDER: PRJNA1140617 | ENA |

REPOSITORIES: ENA

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Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice

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

Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice

Project description:To elicit a dystonia-like phenotype in a genetically predisposed DYT-THAP1 mouse model (Thap1+/-) 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

2025-01-03 | GSE273220 | GEO

Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/- mice

Project description:To elicit a dystonia-like phenotype in a genetically predisposed DYT-THAP1 mouse model (Thap1+/-) by performing a right sciatic nerve crush injury.

2025-01-03 | GSE273219 | GEO

Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice

Project description:Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice

| PRJNA1140619 | ENA

Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/- mice

Project description:Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/- mice

| PRJNA1140620 | ENA

The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [ChIP-Seq]

Project description:The Shieldin complex, consisting of SHLD1, SHLD2, SHLD3 and REV7, shields double strand DNA breaks (DSBs) from nucleolytic resection. The end-protecting activity of Shieldin promotes productive non-homologous end joining (NHEJ) in G1 but can threaten genome integrity during S-phase by blocking homologous recombination (HR). Curiously, the penultimate Shieldin component, SHLD1 is one of the least abundant mammalian proteins. Here, we report that the transcription factors THAP1, YY1 and HCF1 bind directly to the SHLD1 promoter, where they cooperatively maintain the low basal expression of SHLD1. Functionally, this transcriptional network ensures that SHLD1 protein levels are kept in check to enable a proper balance between end protection and end resection during physiological DSB repair. In the context of BRCA1 deficiency, loss of THAP1 dependent SHLD1 expression confers cross resistance to PARP inhibitor and cisplatin, and shorter progression free survival in ovarian cancer patients. In contrast, loss of THAP1 in BRCA2 deficient cells increases genome instability and correlates with improved responses to chemotherapy. Pathogenic THAP1 mutations are causatively linked to adult-onset torsion dystonia type 6 (DYT6) movement disorder, but the critical disease targets are unknown. We further demonstrate that murine models of Thap1-associated dystonia show reduced Shld1 expression concomitant with elevated levels of unresolved DNA damage in the brain. In summary, our study provides the first example of a transcriptional network that directly controls DSB repair choice and reveals a previously unsuspected link between DNA damage and dystonia.

2021-04-13 | GSE154726 | GEO

The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [CRISPR-Cas9 screen]

2021-04-13 | GSE154728 | GEO

The Dystonia Gene THAP1 Controls DNA Double Strand Break Repair Choice [Nascent RNA-seq]

2021-04-13 | GSE154725 | GEO

Peripheral nerve injury induces dystonia-like movements and dysregulation in the energy metabolism: A multi-omics descriptive study in Thap1+/− mice

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

2025-01-03 | GSE273221 | GEO

THAP1 is cell type dependent regulator of SP1 family crucial for dystonic syndromes in human and rat [Striatum_RNA-seq]

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.

2022-09-28 | GSE184959 | GEO

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