X-linked Dystonia-parkinsonism Research Articles

Targeting Myeloperoxidase to Reduce Neuroinflammation in X-Linked Dystonia Parkinsonism.

Although the genetic locus of X-linked dystonia parkinsonism (XDP), a neurodegenerative disease endemic in the Philippines, is well-characterized, the exact mechanisms leading to neuronal loss are not yet fully understood. Recently, we demonstrated an increase in myeloperoxidase (MPO) levels in XDP postmortem prefrontal cortex (PFC), suggesting a role for inflammation in XDP pathogenesis. Therefore, we hypothesized that inhibiting MPO could provide a therapeutic strategy for XDP. MPO activity was measured by using an MPO-activatable fluorescent agent (MAFA) in human postmortem PFC. Reactive oxygen species (ROS) and MPO activity were measured in XDP-derived fibroblasts and SH-SY5Y cells following MPO inhibition. MPO activity was significantly increased in XDP PFC. Additionally, treatment of cell lines with postmortem XDP PFC resulted in a significant increase in ROS levels. To determine whether increases in MPO activity caused increases in ROS, MPO content was immunodepleted from XDP PFC, which resulted in a significant decrease in ROS in SH-SY5Y cells. Consistently, the treatment with verdiperstat, a potent and selective MPO inhibitor, significantly decreased ROS in both XDP-derived fibroblasts and XDP PFC-treated SH-SY5Y cells. Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment.

Dysphagia is a risk factor of malnutrition in X-linked Dystonia-Parkinsonism

Dysphagia is a risk factor of malnutrition in X-linked Dystonia-Parkinsonism

Clinicodemographic and Genetic Modifier Correlation in an X-Linked Dystonia-Parkinsonism Cohort from Mindanao.

X-linked dystonia-parkinsonism (XDP), a neurodegenerative movement disorder endemic to the Philippines, is primarily investigated in patients from Panay Island and the Greater Manila area. However, individuals residing in geographically distant regions may exhibit different clinical or genetic characteristics compared to those documented in earlier reports. The aim was to investigate the relationship of XDP clinical features in a Mindanao cohort with modifiers of age at onset (AAO) variability and utilization of a previously reported AAO model. We investigated clinical and genetic features in 27 XDP patients from southern Mindanao. In all patients, we genotyped the 4 polymorphisms linked to AAO. The XDP-relevant hexanucleotide repeat number significantly correlated with AAO in the 27 patients and explained about 68% of AAO variability. There is no statistical difference between the predicted and actual AAO. The AAO model may provide reliable predictions by employing the effect of XDP genetic modifiers of AAO variability.

Advancements in the Study of Clinical Features and Molecular Functions in Heterogeneous TAF1-associated Clinical Phenotypes

Purpose of review: TATA-binding protein (TBP)-associated factor 1 (TAF1) encodes the largest component of the transcription factor IID (TFIID) complex, which binds to core promoters and serves as a scaffold for assembly of the RNA polymerase II transcription complex. Variants in TAF1 are associated with X-linked dystonia-parkinsonism (XDP) and X-linked syndromic mental retardation-33 (MRXS33). This review provides a concise summary of the genetic and clinicopathological features of TAF1 variants related to phenotype. Recent findings: XDP is an adult-onset X-linked progressive neurodegenerative disorder presenting dystonia and parkinsonism and caused by a SINE-VNTR-Alu (SVA)-type retrotransposon within TAF1. TAF1/MRXS33 intellectual disability syndrome is characterized by global developmental delay, intellectual disability, facial dysmorphia, generalized hypotonia, and neurological abnormalities due to the missense variants in TAF1. Various symptoms of TAF1 missense mutations may be related to mutations in different functional regions of the protein. The clinical manifestations of XDP and MRXS33, both caused by variants of TAF1, present prominent heterogeneity, which could be influenced by whether the TAF1 mutation is located in the coding region, the time when TAF1 expression decreases, and the effect on downstream gene expression. Summary: TAF1 is linked to many different phenotypes because of its variable regulation of coding and noncoding elements, which makes its mechanistic roles in disease challenging to interpret. However, it is important to note that strategies to correct TAF1 splicing could provide therapeutic benefits in different diseases.

G-quadruplexes in an SVA retrotransposon cause aberrant TAF1 gene expression in X-linked dystonia parkinsonism.

G-quadruplexes (G4s) are non-canonical nucleic acid structures that form in guanine (G)-rich genomic regions. X-linked dystonia parkinsonism (XDP) is an inherited neurodegenerative disease in which a SINE-VNTR-Alu (SVA) retrotransposon, characterised by amplification of a G-rich repeat, is inserted into the coding sequence of TAF1, a key partner of RNA polymerase II. XDP SVA alters TAF1 expression, but the cause of this outcome in XDP remains unknown. To assess whether G4s form in XDP SVA and affect TAF1 expression, we first characterised bioinformatically predicted XDP SVA G4s in vitro. We next showed that highly stable G4s can form and stop polymerase amplification at the SVA region from patient-derived fibroblasts and neural progenitor cells. Using chromatin immunoprecipitazion (ChIP)with an anti-G4 antibody coupled tosequencing orquantitativePCR, we showed that XDP SVA G4s are folded even when embedded in a chromatin context in patient-derived cells. Using the G4 ligands BRACO-19 and quarfloxin and total RNA-sequencinganalysis, we showed that stabilisation of the XDP SVA G4s reduces TAF1 transcripts downstream and around the SVA, and increases upstream transcripts, while destabilisation using the G4 unfolderPhpCincreases TAF1 transcripts. Our data indicate that G4 formation in the XDP SVA is a major cause of aberrant TAF1 expression, opening the way for the development of strategies to unfold G4s and potentially target the disease.

The roles of TAF1 in neuroscience and beyond.

The transcriptional machinery is essential for gene expression and regulation; dysregulation of transcription can result in a range of pathologies, including neurodegeneration, cancer, developmental disorders and cardiovascular disease. A key component of RNA polymerase II-mediated transcription is the basal transcription factor IID, which is formed of the TATA box-binding protein (TBP) and 14 TBP-associated factors (TAFs), the largest of which is the TAF1 protein, encoded on the X chromosome (Xq13.1). TAF1 is dysregulated in X-linked dystonia-parkinsonism and congenital mutations in the gene are causative for neurodevelopmental phenotypes; TAF1 dysfunction is also associated with cardiac anomalies and cancer. However, how TAF1 contributes to pathology is unclear. Here, we highlight the key aspects of the TAF1 gene and protein function that may link transcriptional regulation with disorders of development, growth and adult-onset disorders of motor impairment. We highlight the need to experimentally investigate the full range of TAF1 messenger RNA variants and protein isoforms in human and mouse to aid our understanding of TAF1 biology. Furthermore, the X-linked nature of TAF1-related diseases adds complexity to understanding phenotypes. Overall, we shed light on the aspects of TAF1 biology that may contribute to disease and areas that could be addressed for future research and targeted therapeutics.

ZNF91 is an endogenous repressor of the molecular phenotype associated with X-linked dystonia–parkinsonism (XDP)

X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder resulting from an inherited intronic SINE-Alu-VNTR (SVA) retrotransposon in the TAF1 gene that causes dysregulation of TAF1 transcription. The specific mechanism underlying this dysregulation remains unclear, but it is hypothesized to involve the formation of G-quadruplexes (G4) structures within the XDP-SVA that impede transcription. In this study, we show that ZNF91, a critical repressor of SVA retrotransposons, specifically binds to G4-forming DNA sequences. Further, we found that genetic deletion of ZNF91 exacerbates the molecular phenotype associated with the XDP-SVA insertion in patient cells, while no difference was observed when ZNF91 was deleted from isogenic control cells. Additionally, we observed a significant age-related reduction in ZNF91 expression in whole blood and brain, indicating a progressive loss of repression of the XDP-SVA in XDP. These findings indicate that ZNF91 plays a crucial role in controlling the molecular phenotype associated with XDP. Since ZNF91 binds to G4-forming DNA sequences in SVAs, this suggests that interactions between ZNF91 and G4-forming sequences in the XDP-SVA minimize the severity of the molecular phenotype. Our results showing that ZNF91 expression levels significantly decrease with age provide a potential explanation for the age-related progressive neurodegenerative character of XDP. Collectively, our study provides important insights into the protective role of ZNF91 in XDP pathogenesis and suggests that restoring ZNF91 expression, destabilization of G4s, or targeted repression of the XDP-SVA could be future therapeutic strategies to prevent or treat XDP.

Establishing and developing a magnetic resonance-guided focused ultrasound program in a resource-limited setting: the Philippine experience.

Magnetic resonance-guided focused ultrasound (MRgFUS) is a non-invasive lesioning technique used to treat movement disorders such as essential tremor (ET), Parkinson's disease (PD), and X-linked dystonia-parkinsonism (XDP). We would like to report our experience in establishing and developing our MRgFUS program and preliminary results. Adult patients with tremor-dominant PD (TDPD), ET, and XDP were considered for initial screening (neurologic evaluation, skull density ratio [SDR] determination). Eligible patients underwent secondary screening (neurosurgical and neuropsychological evaluation, psychiatric and medical clearance). During the procedure, a neuro-anesthesiologist and neurologist were also present to monitor the patient and perform neurologic evaluation, respectively. Clinical follow-up was scheduled at 2 weeks post-treatment, then at every 3 months. A total of 30 patients underwent MRgFUS treatment: 22 TDPD, 6 XDP, and 2 ET. The mean age was 55.7 years, and majority were male (86.7%). Mean disease duration was 8.6 years. Mean SDR was 0.46. The targets for TDPD and ET were the contralateral ventral intermediate nucleus of the thalamus; for XDP, it was the pallidothalamic tract. The mean maximum temperature was 59.8oC; number of sonocations, 7.3; and treatment time, 64.6min. Majority of patients improved after the procedure. Transient intraprocedural adverse events (headache, dizziness) were reported in 20% of patients while post-procedural events (mild weakness, numbness) were seen in 16.7%. Only 26.7% of patients had follow-up data. Despite the unique challenges encountered, MRgFUS treatment is feasible in resource-limited settings. Additional steps would have to be made to develop and improve the program.

Principal Variables Analysis for Non-Gaussian Data

Principal variables analysis (PVA) is a technique for selecting a subset of variables that capture as much of the information in a dataset as possible. Existing approaches for PVA are based on the Pearson correlation matrix, which is not well-suited to describing the relationships between non-Gaussian variables. We propose a generalized approach to PVA enabling the use of different types of correlation, and we explore using Spearman, Gaussian copula, and polychoric correlations as alternatives to Pearson correlation. We compare performance in simulation studies varying the form of the true multivariate distribution over a range of possibilities. Our results show that on continuous non-Gaussian data, using generalized PVA with Gaussian copula or Spearman correlations provides a major improvement in performance compared to Pearson. On ordinal data, generalized PVA with polychoric correlations outperforms the rest by a wide margin. We apply generalized PVA to a dataset of 102 clinical variables measured on individuals with X-linked dystonia parkinsonism (XDP), a neurodegenerative disorder involving symptoms of both dystonia and parkinsonism. We find that using different types of correlation yields substantively different sets of principal variables; for example, parkinsonism-related metrics appear more explanatory than dystonia-related metrics on the observed data. Supplementary materials for this article are available online.

Taf1 knockout is lethal in embryonic male mice and heterozygous females show weight and movement disorders.

The TATA box-binding protein-associated factor 1 (TAF1) is a ubiquitously expressed protein and the largest subunit of the basal transcription factor TFIID, which plays a key role in initiation of RNA polymerase II-dependent transcription. TAF1 missense variants in human males cause X-linked intellectual disability, a neurodevelopmental disorder, and TAF1 is dysregulated in X-linked dystonia-parkinsonism, a neurodegenerative disorder. However, this field has lacked a genetic mouse model of TAF1 disease to explore its mechanism in mammals and treatments. Here, we generated and validated a conditional cre-lox allele and the first ubiquitous Taf1 knockout mouse. We discovered that Taf1 deletion in male mice was embryonically lethal, which may explain why no null variants have been identified in humans. In the brains of Taf1 heterozygous female mice, no differences were found in gross structure, overall expression and protein localisation, suggesting extreme skewed X inactivation towards the non-mutant chromosome. Nevertheless, these female mice exhibited a significant increase in weight, weight with age, and reduced movement, suggesting that a small subset of neurons was negatively impacted by Taf1 loss. Finally, this new mouse model may be a future platform for the development of TAF1 disease therapeutics.

Targeting myeloperoxidase to reduce neuroinflammation in X-linked dystonia parkinsonism.

MPO activity is increased in XDP post-mortem prefrontal cortex.MPO activity is increased in cellular models of XDP.MPO increases reactive oxygen species (ROS) in vitro.Inhibiting MPO mitigates ROS in XDP.The MPO inhibitor, verdiperstat, dampens ROS suggesting a potential therapeutic strategy for XDP.

Motor assessment of X-linked dystonia parkinsonism via machine-learning-based analysis of wearable sensor data

X-linked dystonia parkinsonism (XDP) is a neurogenetic combined movement disorder involving both parkinsonism and dystonia. Complex, overlapping phenotypes result in difficulties in clinical rating scale assessment. We performed wearable sensor-based analyses in XDP participants to quantitatively characterize disease phenomenology as a potential clinical trial endpoint. Wearable sensor data was collected from 10 symptomatic XDP patients and 3 healthy controls during a standardized examination. Disease severity was assessed with the Unified Parkinson’s Disease Rating Scale Part 3 (MDS-UPDRS) and Burke-Fahn-Marsden dystonia scale (BFM). We collected sensor data during the performance of specific MDS-UPDRS/BFM upper- and lower-limb motor tasks, and derived data features suitable to estimate clinical scores using machine learning (ML). XDP patients were at varying stages of disease and clinical severity. ML-based algorithms estimated MDS-UPDRS scores (parkinsonism) and dystonia-specific data features with a high degree of accuracy. Gait spatio-temporal parameters had high discriminatory power in differentiating XDP patients with different MDS-UPDRS scores from controls, XDP freezing of gait, and dystonic/non-dystonic gait. These analyses suggest the feasibility of using wearable sensor data for deriving reliable clinical score estimates associated with both parkinsonian and dystonic features in a complex, combined movement disorder and the utility of motion sensors in quantifying clinical examination.

Islands and Neurology: An Exploration into a Unique Association.

The current study investigates the intricate connection between neurology and islands shedding light on the historical, epidemiological, and genetic aspects. Based on an elaborate literature review, we identified neurological conditions having a significant clustering in an island(s), confined to a particular island(s), named after an island, and described first in an island. The genetic factors played a crucial role, uncovering disorders like Cayman ataxia, Machado Joseph disease, SGCE-mediated dystonia-myoclonus syndrome, X-linked dystonia parkinsonism, hereditary transthyretinrelated amyloidosis, Charcot Marie Tooth 4F, and progressive myoclonic epilepsy syndromes, that exhibited remarkable clustering in diverse islands. Local customs also left enduring imprints. Practices such as cannibalism in Papua New Guinea led to Kuru, while cycad seed consumption in Guam triggered Lytico-Bodig disease. Toxin-mediated neurologic disorders exhibited intricate island connections, exemplified by Minamata disease in Kyushu islands and atypical parkinsonism in French Caribbean islands. Additionally, the Cuban epidemic of amblyopia and neuropathy was associated with severe nutritional deficiencies. This study pioneers a comprehensive review narrating the genetic, environmental, and cultural factors highlighting the spectrum of neurological disorders in island settings. It enriches the medical literature with a unique understanding of the diverse influences shaping neurological health in island environments.

Mini-heterochromatin domains constrain the cis-regulatory impact of SVA transposons in human brain development and disease.

SVA (SINE (short interspersed nuclear element)-VNTR (variable number of tandem repeats)-Alu) retrotransposons remain active in humans and contribute to individual genetic variation. Polymorphic SVA alleles harbor gene regulatory potential and can cause genetic disease. However, how SVA insertions are controlled and functionally impact human disease is unknown. Here we dissect the epigenetic regulation and influence of SVAs in cellular models of X-linked dystonia parkinsonism (XDP), a neurodegenerative disorder caused by an SVA insertion at the TAF1 locus. We demonstrate that the KRAB zinc finger protein ZNF91 establishes H3K9me3 and DNA methylation over SVAs, including polymorphic alleles, in human neural progenitor cells. The resulting mini-heterochromatin domains attenuate the cis-regulatory impact of SVAs. This is critical for XDP pathology; removal of local heterochromatin severely aggravates the XDP molecular phenotype, resulting in increased TAF1 intron retention and reduced expression. Our results provide unique mechanistic insights into how human polymorphic transposon insertions are recognized and how their regulatory impact is constrained by an innate epigenetic defense system.

Stability of Mosaic Divergent Repeat Interruptions in X-Linked Dystonia-Parkinsonism.

X-Linked dystonia-parkinsonism (XDP) is an adult-onset neurodegenerative disorder characterized by rapidly progressive dystonia and parkinsonism. Mosaic Divergent Repeat Interruptions affecting motif Length and Sequence (mDRILS) were recently found within the TAF1 SVA repeat tract and were shown to associate with repeat stability and age at onset in XDP, specifically the AGGG [5'-SINE-VNTR-Alu(AGAGGG)2AGGG(AGAGGG)n] mDRILS. This study aimed to investigate the stability of mDRILS frequencies and stability of (AGAGGG)n repeat length during transmission in parent-offspring pairs. Fifty-six families (n = 130) were investigated for generational transmission of repeat length and mDRILS. The mDRILS stability of 16 individuals was assessed at two sampling points 1 year apart. DNA was sequenced with long-read technologies after long-range polymerase chain reaction amplification of the TAF1 SVA. Repeat number and mDRILS were detected with Noise-Cancelling Repeat Finder (NCRF). When comparing the repeat domain, 51 of 65 children had either contractions or expansions of the repeat length. The AGGG frequency remained stable across generations at 0.074 (IQR: 0.069-0.078) (z = -0.526; P = 0.599). However, the median AGGG frequency in children with an expansion (0.072 [IQR: 0.066-0.076]) was lower compared with children with retention or contraction (0.080 [IQR: 0.073-0.083]) (z = -0.007; P = 0.003). In a logistic regression model, the AGGG frequency predicted the outcome of either expansion or retention/contraction when including repeat number and sex as covariates (β = 80.7; z-score = 2.63; P = 0.0085). The AGGG frequency varied slightly over 1 year (0.070 [IQR: 0.063-0.080] to 0.073 [IQR: 0.069-0.078]). Our results show that a higher AGGG frequency may stabilize repeats across generations. This highlights the importance of further investigating mDRILS as a disease-modifying factor with generational differences. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuroenergetic Changes in Patients with X-Linked Dystonia-Parkinsonism and Female Carriers.

X-linked dystonia-parkinsonism (XDP) is a rare movement disorder characterized by profound neurodegeneration in the basal ganglia. The molecular consequences and the bioenergetic state of affected individuals remain largely unexplored. To investigate the bioenergetic state in male patients with XDP and female carriers using 31phosphorus magnetic resonance spectroscopy imaging and to correlate these findings with clinical manifestations. We examined the levels of high-energy phosphorus-containing metabolites (HEP) in the basal ganglia and cerebellum of five male patients with XDP, 10 asymptomatic female heterozygous carriers, and 10 SVA-insertion-free controls. HEP levels were reduced in the basal ganglia of patients with XDP (PwXDP) compared to controls, but increased in the cerebellum of both male patients and female carriers. Our findings suggest a potential compensatory mechanism in the cerebellum of female carriers regardless of sex. Our study highlights alterations in HEP levels in PwXDP patients and female carriers.

Full body autopsy of a male patient with known X-linked dystonia parkinsonism

Full body autopsy of a male patient with known X-linked dystonia parkinsonism

Proteomic analysis of X-linked dystonia parkinsonism disease striatal neurons reveals altered RNA metabolism and splicing

X-linked dystonia-parkinsonism (XDP) is a rare neurodegenerative disease endemic to the Philippines. The genetic cause for XDP is an insertion of a SINE-VNTR-Alu (SVA)-type retrotransposon within intron 32 of TATA-binding protein associated factor 1 (TAF1) that causes an alteration of TAF1 splicing, partial intron retention, and decreased transcription. Although TAF1 is expressed in all organs, medium spiny neurons (MSNs) within the striatum are one of the cell types most affected in XDP. To define how mutations in the TAF1 gene lead to MSN vulnerability, we carried out a proteomic analysis of human XDP patient-derived neural stem cells (NSCs) and MSNs derived from induced pluripotent stem cells. NSCs and MSNs were grown in parallel and subjected to quantitative proteomic analysis in data-independent acquisition mode on the Orbitrap Eclipse Tribrid mass spectrometer. Subsequent functional enrichment analysis demonstrated that neurodegenerative disease-related pathways, such as Huntington's disease, spinocerebellar ataxia, cellular senescence, mitochondrial function and RNA binding metabolism, were highly represented. We used weighted coexpression network analysis (WGCNA) of the NSC and MSN proteomic data set to uncover disease-driving network modules. Three of the modules significantly correlated with XDP genotype when compared to the non-affected control and were enriched for DNA helicase and nuclear chromatin assembly, mitochondrial disassembly, RNA location and mRNA processing. Consistent with aberrant mRNA processing, we found splicing and intron retention of TAF1 intron 32 in XDP MSN. We also identified TAF1 as one of the top enriched transcription factors, along with YY1, ATF2, USF1 and MYC. Notably, YY1 has been implicated in genetic forms of dystonia. Overall, our proteomic data set constitutes a valuable resource to understand mechanisms relevant to TAF1 dysregulation and to identify new therapeutic targets for XDP.

Applicability of clinical genetic testing for deep brain stimulation treatment in monogenic Parkinson's disease and monogenic dystonia: a multidisciplinary team perspective.

In this perspective article, we highlight the possible applicability of genetic testing in Parkinson's disease and dystonia patients treated with deep brain stimulation (DBS). DBS, a neuromodulatory technique employing electrical stimulation, has historically targeted motor symptoms in advanced PD and dystonia, yet its precise mechanisms remain elusive. Genetic insights have emerged as potential determinants of DBS efficacy. Known PD genes such as GBA, SNCA, LRRK2, and PRKN are most studied, even though further studies are required to make firm conclusions. Variable outcomes depending on genotype is present in genetic dystonia, as DYT-TOR1A, NBIA/DYTPANK2, DYT-SCGE and X-linked dystonia-parkinsonism have demonstrated promising outcomes following GPi-DBS, while varying outcomes have been documented in DYT-THAP1. We present two clinical vignettes that illustrate the applicability of genetics in clinical practice, with one PD patient with compound GBA mutations and one GNAL dystonia patient. Integrating genetic testing into clinical practice is pivotal, particularly with advancements in next-generation sequencing. However, there is a clear need for further research, especially in rarer monogenic forms. Our perspective is that applying genetics in PD and dystonia is possible today, and despite challenges, it has the potential to refine patient selection and enhance treatment outcomes.

Isolated lingual dystonia as a presenting symptom of X-linked dystonia parkinsonism

Isolated lingual dystonia as a presenting symptom of X-linked dystonia parkinsonism