Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism
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PROVIDER: PRJNA430958 | ENA |
REPOSITORIES: ENA
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Project description:Genetics, Cellular and Natural History of X-Linked Dystonia Parkinsonism
| PRJNA430957 | ENA
Project description:X-linked dystonia parkinsonism is a neurodegenerative movement disorder that affects men whose mothers originate from the island of Panay, Philippines. Current evidence indicates that the most likely cause is an expansion in the TAF1 gene that may be amenable to treatment. To prepare for clinical trials of therapeutic candidates for X-linked dystonia parkinsonism, we focused on the identification of quantitative phenotypic measures that are most strongly associated with disease progression. Our main objective is to establish a comprehensive, quantitative assessment of movement dysfunction and bulbar motor impairments that are sensitive and specific to disease progression in persons with X-linked dystonia parkinsonism. These measures will set the stage for future treatment trials. We enrolled patients with X-linked dystonia parkinsonism and performed a comprehensive oromotor, speech and neurological assessment. Measurements included patient-reported questionnaires regarding daily living activities and both neurologist-rated movement scales and objective quantitative measures of bulbar function and nutritional status. Patients were followed for 18 months from the date of enrollment and evaluated every 6 months during that period. We analysed a total of 87 men: 29 were gene-positive and had symptoms at enrollment, seven were gene-positive and had no symptoms at enrollment and 51 were gene-negative. We identified measures that displayed a significant change over the study. We used principal variables analysis to identify a minimal battery of 21 measures that explains 67.3% of the variance over the course of the study. These measures included patient-reported, clinician-rated and objective quantitative outcomes that may serve as endpoints in future clinical trials.
| S-EPMC10231801 | biostudies-literature
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
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.
2020-05-26 | PXD009905 | Pride
Project description:Investigation of expression profile in XDP brains. Keywords: an XDP patient and neurologically normal control
2006-02-03 | GSE3064 | GEO
Project description:G-quadruplexes within the SVA retrotransposon modulate TAF1 gene expression in X-linked Dystonia Parkinsonism
| PRJNA1053312 | ENA
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
Project description:Cerebellar Dysfunction in a Mouse Model of Childhood-Onset Manganese-Induced Dystonia Parkinsonism
| PRJNA1297174 | ENA
Project description:<p>X-linked Dystonia-Parkinsonism (XDP) is a long-standing quandary in human disease genetics. XDP is predominantly observed on Panay island in the Philippines. This study is one of the first of its kind to interrogate an unsolved Mendelian disorder by integrating genome and transcriptome assembly methods using Illumina, 10X Genomics, Pacific Biosciences, and Agilent genome targeting technologies. These data provide strong evidence for a pathogenic link between a noncoding SVA retrotransposon and XDP. We demonstrate that this Mendelian disorder is associated with a sine-VNTR-Alu (SVA) retrotransposon that inserted into the TAF1 gene and is shared by all XDP probands, yet never observed in controls from worldwide populations. Transcriptome assembly in iPSC-derived neural stem cells (NSCs) and neurons revealed that this SVA caused aberrant splicing and significant intron retention, which was negatively correlated with TAF1 expression. Remarkably, CRISPR/Cas9 excision of the SVA rescued the aberrant transcriptional signature and normalized expression of TAF1 in patient-derived NSCs.</p>
| phs001525 | dbGaP
Project description:X-linked dystonia-parkinsonism (XDP; OMIM314250), also referred to as DYT3 dystonia or "Lubag" disease, was first described as an endemic disease in the Philippine island of Panay. XDP is an adult-onset movement disorder characterized by progressive and severe dystonia followed by overt parkinsonism in the later years of life. Among the primary monogenic dystonias, XDP has been identified as a transcriptional dysregulation syndrome with impaired expression of the TAF1 (TATA box-binding protein associated factor 1) gene, which is a critical component of the cellular transcription machinery. The major neuropathology of XDP is progressive neuronal loss in the neostriatum (i.e., the caudate nucleus and putamen). XDP may be used as a human disease model to elucidate the pathomechanisms by which striatal neurodegeneration leads to dystonia symptoms. In this article, we introduce recent advances in the understanding of the interplay between pathophysiology and genetics in XDP.
| S-EPMC5532585 | biostudies-literature