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Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism

ABSTRACT: Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism

PROVIDER: PRJNA430958 | ENA |

REPOSITORIES: ENA

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Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism

Project description:Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism

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Mitochondrial toxins cause widespread downregulation of pathways in X-linked dystonia-parkinsonism patient-derived neurons

Project description:The genetic mechanism underlying the neurodegenerative movement disorder X-linked dystonia-parkinsonism (XDP) involves a retrotransposon insertion within the TAF1 gene. TAF1 encodes the TATA-box binding protein-associated factor 1, the largest subunit of the basal transcription factor TFIID, which connects transcription activation to the assembly of the RNA polymerase II preinitiation complex at the core promoter of genes. This study investigated how the TAF1 mutation affects the transcriptomes of XDP patient-derived neurons under basal conditions and in response to mitochondrial toxins.

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Establishing a natural history of X-linked dystonia parkinsonism.

Project description: Not available

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Alterations in energy production in a Drosophila model for the X-linked dystonia-parkinsonism-related Taf1 deficiency

Project description:Background: X-linked dystonia-parkinsonism (XDP), an adult-onset neurodegenerative disorder, is caused by an SVA insertion in the TAF1 gene, containing a hexanucleotide, the length of which is correlated to the severity of the disease. The SVA insertion moderately disrupts gene expression; however, the underlying disease mechanism remains enigmatic. Methods: Here, we characterized a fly model for Taf1 deficiency and performed a pilot RNA sequencing analysis. Subsequently, we validated these findings in Taf1-deficient flies and in XDP patient-derived fibroblasts. Results: We identified an upregulation of genes involved in lipid-dependent energy production as a compensatory mechanism to maintain proper ATP levels. However, studies in XDP patient-derived fibroblasts with minor TAF1 reduction did not confirm these findings. Conclusion: β-oxidation is elevated in flies with severe TAF1 reduction but not detected in XDP-patient fibroblasts, suggesting that this compensatory mechanism may only manifest above a critical TAF1 dosage threshold, absent in patient basal conditions. This finding thus suggests that dosage-dependent metabolic responses occur following TAF1 loss.

2026-02-09 | GSE318289 | GEO

G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism [RNA-Seq]

Project description:X-linked dystonia parkinsonism (XDP) is an inherited neurodegenerative disease characterized by the antisense insertion of an SVA retrotransposon into the TAF1 gene, encoding for the largest subunit of the basal transcription factor TFIID, which is essential for RNA polymerase II activity. This SVA insertion has been associated with altered TAF1 expression levels, but the cause of this outcome and its link to the development of XDP remain unknown. Unique to the XDP SVA compared to other SVA retrotransposons in the human genome is the amplification of the (GGGAGA)n repeat domain, creating a unique G4-prone region, whose length correlates with age at onset and disease severity. By ChIP-seq and ChIP-qPCR with the anti-G4 antibody BG4, we assessed that G4s are present in the folded state in the XDP SVA of these cells. Using available G4 ligands, we demonstrated that stabilization of the XDP SVA G4s reduces TAF1 transcripts in the exons around and downstream of the SVA, while increasing the transcription of the upstream exons, possibly through a positive feedback loop.

2024-09-04 | GSE250293 | GEO

SRRM4/nSR100 directs neuronal-specific microexon splicing of TAF1 mRNA involved in X-linked Dystonia-Parkinsonism

Project description:X-linked dystonia-parkinsonism is a neurodegenerative disease, which is caused by a SVA retrotransposon insertion within TAF1, gene encoding an integral component of the basal transcription factor TFIID. The SVA insertion has been shown to induce defects both in biosynthesis and in alternative splicing of TAF1 mRNA in various cell types. This includes the reduction of a neuron-specific isoform of TAF1 mRNA generated by inclusion of the evolutionary conserved microexon 34’ (TAF1-34’). In this study, we investigated the tissue distribution of TAF1-34’ mRNA and protein and the neuron-specific mechanism sustaining its alternative splicing. Using isoform-specific RNA probes and antibodies, we observe that canonical TAF1 and TAF1-34’ have different distributions in the brain. To our knowledge, this is the first in situ detection of a microexon. We find that the differential expression of these two isoforms distinguishes proliferating from post-mitotic neurons in vitro and in vivo. Knockdown and ectopic expression experiments in cell lines demonstrated that the neuron-specific splicing factor nSR100/SRRM4 is directing the inclusion of microexon 34’ into TAF1 mRNA. These results show that SRRM4 regulates temporal and spatial distribution of alternative TAF1 mRNAs to generate a neuron-specific isoform of basal transcription factor TFIID.

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X linked dystonia parkinsonism

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G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism

Project description:G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism

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Mitochondrial toxins cause widespread downregulation of pathways in X-linked dystonia-parkinsonism patient-derived neurons

Project description:Mitochondrial toxins cause widespread downregulation of pathways in X-linked dystonia-parkinsonism patient-derived neurons

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Cerebellar Dysfunction in a Mouse Model of Childhood-Onset Manganese-Induced Dystonia Parkinsonism

Project description:Humans with pathogenic variants in the manganese (Mn) transporter gene SLC39A14 exhibit highly elevated brain Mn concentrations and childhood-onset dystonia-parkinsonism. Here we show that Slc39a14-knockout (KO) mice, a preclinical model of the disease, express deficits in physiological tremor implicating cerebellar (CB) dysfunction in the presence of elevated CB Mn levels. Imaging of intracellular Mn levels using synchrotron-based X-ray fluorescence microscopy revealed highly increased Mn concentrations in Purkinje cells (PCs). We performed RNAseq studies to determine biological pathways altered in the CB of Slc39a14-KO mice relative to wildtype (WT), which revealed an upregulation of pathways and genes responsible for immune response and cell death. To confirm these findings, we performed quantitative autoradiography of the neuroinflammation biomarker Translocator Protein 18kDa (TSPO) which was significantly increased in the CB of Slc39a14-KO mice relative to WT and was further confirmed with Iba-1 positive microglia activation and clustering in the CB cortex. Immunostaining for cleaved caspase-3 (cCASP3), a marker of apoptosis, revealed a widespread increase in cCASP3 immunoreactivity in PCs, which was supported by Hematoxylin and Eosin (H&E) staining demonstrating pyknotic PCs. Lastly, functional electrophysiological assessment of CB neurocircuitry revealed marked decrease in firing rates of cerebellar nuclei (CN) neurons and an increase in variability of PCs simple spikes firing. These findings show, for the first time, Mn-induced PCs degeneration in the CB of Slc39a14-KO mice and provide a pathological substrate for the dystonia-like movement, balance, and gait abnormalities in SLC39A14 mutation carriers.

2025-08-01 | GSE303733 | GEO

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