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Movement Disorders : Official Journal... Jan 2021X-linked dystonia-parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to...
BACKGROUND
X-linked dystonia-parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full-length mRNA transcript.
OBJECTIVES
The objective of this study was to discover cell-based and biofluid-based biomarkers for X-linked dystonia-parkinsonism.
METHODS
RNA from patient-derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet-digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5' and 3' to the retrotransposon insertion and the disease-specific splice variant TAF1-32i in whole-blood RNA. Plasma levels of neurofilament light chain were measured using single-molecule array.
RESULTS
In neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1-3'/5' ratio was lower in patient samples, whereas TAF1-32i expression is higher relative to controls. In whole-blood RNA, both TAF1-3'/5' ratio and TAF1-32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79.
CONCLUSIONS
TAF1 dysregulation in blood serves as a disease-specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Adult; Biomarkers; Dystonic Disorders; Genetic Diseases, X-Linked; Histone Acetyltransferases; Humans; Intermediate Filaments; Male; TATA-Binding Protein Associated Factors; Transcription Factor TFIID
PubMed: 32975318
DOI: 10.1002/mds.28305 -
Journal of the Royal College of... Oct 1970
Review
Topics: Age Factors; Antipsychotic Agents; Basal Ganglia Diseases; Central Nervous System Stimulants; Child; Diagnosis, Differential; Dose-Response Relationship, Drug; Dystonia Musculorum Deformans; Female; Humans; Male; Movement Disorders; Parasympatholytics; Parkinson Disease, Secondary; Phenothiazines; Sex Factors; Tranquilizing Agents
PubMed: 4150143
DOI: No ID Found -
Movement Disorders : Official Journal... Nov 2013The pathogenesis and the genetic basis of adult-onset primary torsion dystonia remain poorly understood. Because of markedly reduced penetrance in this disorder, a...
The pathogenesis and the genetic basis of adult-onset primary torsion dystonia remain poorly understood. Because of markedly reduced penetrance in this disorder, a number of endophenotypes have been proposed; many of these may be epiphenomena secondary to disease manifestation. Mediational endophenotypes represent gene expression; the study of trait (endophenotypic) rather than state (phenotypic) characteristics avoids the misattribution of secondary adaptive cerebral changes to pathogenesis. We argue that abnormal temporal discrimination is a mediational endophenotype; its use facilitates examination of the effects of age, gender, and environment on disease penetrance in adult-onset dystonia. Using abnormal temporal discrimination in unaffected first-degree relatives as a marker for gene mutation carriage may inform exome sequencing techniques in families with few affected individuals. We further hypothesize that abnormal temporal discrimination reflects dysfunction in an evolutionarily conserved subcortical-basal ganglia circuit for the detection of salient novel environmental change. The mechanisms of dysfunction in this pathway should be a focus for future research in the pathogenesis of adult-onset primary torsion dystonia.
Topics: Adult; Discrimination, Psychological; Dystonia; Humans; Phenotype
PubMed: 24108447
DOI: 10.1002/mds.25676 -
Biochimica Et Biophysica Acta.... Aug 2021The Endoplasmic Reticulum (ER) is responsible for the folding and post-translational modification of secretory proteins, as well as for triaging misfolded proteins....
The Endoplasmic Reticulum (ER) is responsible for the folding and post-translational modification of secretory proteins, as well as for triaging misfolded proteins. During folding, there is a complex yet only partially understood interplay between disulfide bond formation, which is an enzyme catalyzed event in the oxidizing environment of the ER, along with other post-translational modifications (PTMs) and chaperone-supported protein folding. Here, we used the glycoprotein torsinA as a model substrate to explore the impact of ER redox homeostasis on PTMs and protein biogenesis. TorsinA is a AAA+ ATPase with unusual oligomeric properties and controversial functions. The deletion of a C-terminal glutamic acid residue (∆E) is associated with the development of Early-Onset Torsion Dystonia, a severe movement disorder. TorsinA differs from other AAA+ ATPases since it is an ER resident, and as a result of its entry into the ER torsinA contains two N-linked glycans and at least one disulfide bond. The role of these PTMs on torsinA biogenesis and function and the identity of the enzymes that catalyze them are poorly defined. Using a yeast torsinA expression system, we demonstrate that a specific protein disulfide isomerase, Pdi1, affects the folding and N-linked glycosylation of torsinA and torsinA∆E in a redox-dependent manner, suggesting that the acquisition of early torsinA folding intermediates is sensitive to perturbed interactions between Cys residues and the quality control machinery. We also highlight the role of specific Cys residues during torsinA biogenesis and demonstrate that torsinA∆E is more sensitive than torsinA when these Cys residues are mutated.
Topics: Adenosine Triphosphatases; Endoplasmic Reticulum; Glycosylation; Homeostasis; Models, Molecular; Oxidation-Reduction; Protein Processing, Post-Translational; Saccharomyces cerevisiae Proteins
PubMed: 34062155
DOI: 10.1016/j.bbamcr.2021.119073 -
Neuron Dec 2005Mutations in torsinA cause dominantly inherited early-onset torsion dystonia in humans. In this issue of Neuron, Goodchild et al. show that torsinA knockout and knockin... (Review)
Review
Mutations in torsinA cause dominantly inherited early-onset torsion dystonia in humans. In this issue of Neuron, Goodchild et al. show that torsinA knockout and knockin mice have similar phenotypes, which suggests that the mutant torsinA allele causes disease because it has decreased function. The experiments also highlight the possible role of nuclear envelope dynamics in maintaining normal neuronal function.
Topics: Animals; Brain; Cell Differentiation; Disease Models, Animal; Dystonia Musculorum Deformans; Humans; Mice; Molecular Chaperones; Mutation; Neurons; Nuclear Envelope; Phenotype
PubMed: 16364891
DOI: 10.1016/j.neuron.2005.12.006 -
Tremor and Other Hyperkinetic Movements... 2015Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of... (Review)
Review
BACKGROUND
Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste.
RESULTS
In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called "simple mannerisms, childish behaviour or fake pathological movements" was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud's pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim's 1911 seminal description of dystonia musculorum deformans in Berlin.
DISCUSSION
Brissaud-Meige's misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970-1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society's classification of dystonia.
PubMed: 26417535
DOI: 10.7916/D8KD1X74 -
Journal of Medical Genetics Dec 1981The results of a postal questionnaire distributed to British members of Mensa failed to confirm an association of superior intelligence with torsion dystonia,...
The results of a postal questionnaire distributed to British members of Mensa failed to confirm an association of superior intelligence with torsion dystonia, retinoblastoma, or phenylketonuria, but were consistent with real associations between high IQ and infantile autism, gout, and myopia. Further confirmation of these findings in other populations might well indicate that genes producing these disorders have more or less direct effects on cerebral development and function.
Topics: Adult; Autistic Disorder; Dystonia; Female; Gene Frequency; Genetic Testing; Gout; Humans; Intelligence; Male; Myopia; Phenylketonurias; Retinoblastoma; Sex Factors
PubMed: 7334499
DOI: 10.1136/jmg.18.6.410 -
Beijing Da Xue Xue Bao. Yi Xue Ban =... Feb 2006Dystonia is a syndrome which is characterized by sustained muscle contractions, producing twisting, repetitive, and patterned movements, or abnormal postures. According... (Review)
Review
Dystonia is a syndrome which is characterized by sustained muscle contractions, producing twisting, repetitive, and patterned movements, or abnormal postures. According to genetic basis, dystonia is classified into 13 subtypes. We mainly discussed two subtypes, DYT1 and DYT5, in this review. Early-onset primary dystonia is caused by the mutation of DYT1 gene, which leads to TORSINA abnormal. GTP cyclohydrolase 1 (GTPCH1)-deficient DRD (DYT5) is caused by the mutations of GCH1 gene. By genetic testing, we can confirm clinical diagnosis of each subtype and develop prenatal diagnosis for it.
Topics: Dystonia Musculorum Deformans; Humans
PubMed: 16415980
DOI: No ID Found -
Experimental Neurology Aug 2008A three-base-pair deletion in the torsinA gene leads to generalized torsion dystonia (DYT1) in humans, an often devastating movement disorder in which voluntary... (Review)
Review
A three-base-pair deletion in the torsinA gene leads to generalized torsion dystonia (DYT1) in humans, an often devastating movement disorder in which voluntary movements are disrupted by sustained muscle spasms and abnormal limb posturing. In a recent issue of Experimental Neurology, Zhao et al. (2008) have provided a thorough behavioral, anatomic, and biochemical characterization of a mouse line that over-expresses human mutant torsinA, with particular emphasis on the possible role of dopaminergic dysfunction in these animals. This commentary provides an overview of the clinical and genetic features of the human disease and of the available transgenic mouse models for DYT1 dystonia, and discusses the evidence favoring the role of dopamine in the clinical manifestations of the disease.
Topics: Animals; Disease Models, Animal; Dopamine; Dystonic Disorders; Humans; Molecular Chaperones
PubMed: 18513716
DOI: 10.1016/j.expneurol.2008.04.020 -
Neurobiology of Disease Jan 2024X-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...
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.
Topics: Humans; Dystonia; Neurodegenerative Diseases; Proteomics; Transcription Factor TFIID; Dystonic Disorders; Neurons; RNA, Messenger; Parkinsonian Disorders
PubMed: 38042508
DOI: 10.1016/j.nbd.2023.106367