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Behavioural Brain Research Feb 2023DYT1 or DYT-TOR1A dystonia is early-onset generalized dystonia caused by a trinucleotide deletion of GAG in the TOR1A or DYT1 gene leads to the loss of a glutamic acid...
DYT1 or DYT-TOR1A dystonia is early-onset generalized dystonia caused by a trinucleotide deletion of GAG in the TOR1A or DYT1 gene leads to the loss of a glutamic acid residue in the resulting torsinA protein. A mouse model with overt dystonia is of unique importance to better understand the DYT1 pathophysiology and evaluate preclinical drug efficacy. DYT1 dystonia is likely a network disorder involving multiple brain regions, particularly the basal ganglia. Tor1a conditional knockout in the striatum or cerebral cortex leads to motor deficits, suggesting the importance of corticostriatal connection in the pathogenesis of dystonia. Indeed, corticostriatal long-term depression impairment has been demonstrated in multiple targeted DYT1 mouse models. Pappas and colleagues developed a conditional knockout line (Dlx-CKO) that inactivated Tor1a in the forebrain and surprisingly displayed overt dystonia. We set out to validate whether conditional knockout affecting both cortex and striatum would lead to overt dystonia and whether machine learning-based video behavioral analysis could be used to facilitate high throughput preclinical drug screening. We generated Dlx-CKO mice and found no overt dystonia or motor deficits at 4 months. At 8 months, retesting revealed motor deficits in rotarod, beam walking, grip strength, and hyperactivity in the open field; however, no overt dystonia was visually discernible or through the machine learning-based video analysis. Consistent with other targeted DYT1 mouse models, we observed age-dependent deficits in the beam walking test, which is likely a better motor behavioral test for preclinical drug testing but more labor-intensive when overt dystonia is absent.
Topics: Mice; Animals; Dystonia; Mice, Knockout; Dystonia Musculorum Deformans; Prosencephalon; Disease Models, Animal; Molecular Chaperones
PubMed: 36417958
DOI: 10.1016/j.bbr.2022.114221 -
Frontiers in Systems Neuroscience 2023The normal hemispheric balance can be altered by the asymmetric sensorimotor signal elicited by Cervical Dystonia (CD), leading to motor and cognitive deficits.
INTRODUCTION
The normal hemispheric balance can be altered by the asymmetric sensorimotor signal elicited by Cervical Dystonia (CD), leading to motor and cognitive deficits.
METHODS
Directional errors, peak velocities, movement and reaction times of pointing towards out-of-reach targets in the horizontal plane were analysed in 18 CD patients and in 11 aged-matched healthy controls.
RESULTS
CD patients displayed a larger scatter of individual trials around the average pointing direction (variable error) than normal subjects, whatever the arm used, and the target pointed. When pointing in the left hemispace, all subjects showed a left deviation (constant error) with respect to the target position, which was significantly larger in CD patients than controls, whatever the direction of the abnormal neck torsion could be. Reaction times were larger and peak velocities lower in CD patients than controls.
DISCUSSION
Deficits in the pointing precision of CD patients may arise from a disruption of motor commands related to the sensorimotor imbalance, from a subtle increase in shoulder rigidity or from a reduced agonists activation. Their larger left bias in pointing to left targets could be due to an increased right parietal dominance, independently upon the direction of head roll/jaw rotation which expands the left space representation and/or increases left spatial attention. These deficits may potentially extend to tracking and gazing objects in the left hemispace, leading to reduced skills in spatial-dependent motor and cognitive performance.
PubMed: 38090048
DOI: 10.3389/fnsys.2023.1306387 -
Neuroscience Nov 2009Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary... (Review)
Review
Primary torsion dystonia (PTD) is a chronic movement disorder manifested clinically by focal or generalized sustained muscle contractions, postures, and/or involuntary movements. The most common inherited form of PTD is associated with the DYT1 mutation on chromosome 9q34. A less frequent form is linked to the DYT6 locus on chromosome 8q21-22. Both forms are autosomal dominant with incomplete (approximately 30%) clinical penetrance. Extensive functional and microstructural imaging with positron emission tomography (PET) and diffusion tensor MRI (DTI) has been performed on manifesting and non-manifesting carriers of these mutations. The results are consistent with the view of PTD as a neurodevelopmental circuit disorder involving cortico-striatal-pallido-thalamocortical (CSPTC) and related cerebellar-thalamo-cortical pathways. Studies of resting regional metabolism have revealed consistent abnormalities in PTD involving multiple interconnected elements of these circuits. In gene carriers, changes in specific subsets of these regions have been found to relate to genotype, phenotype, or both. For instance, genotypic abnormalities in striatal metabolic activity parallel previously reported reductions in local D(2) receptor availability. Likewise, we have identified a unique penetrance-related metabolic network characterized by increases in the pre-supplementary motor area (SMA) and parietal association areas, associated with relative reductions in the cerebellum, brainstem, and ventral thalamus. Interestingly, metabolic activity in the hypermetabolic areas has recently been found to be modified by the penetrance regulating D216H polymorphism. The DTI data raise the possibility that metabolic abnormalities in mutation carriers reflect adaptive responses to developmental abnormalities in the intrinsic connectivity of the motor pathways. Moreover, findings of increased motor activation responses in these subjects are compatible with the reductions in cortical inhibition that have been observed in this disorder. Future research will focus on clarifying the relationship of these changes to clinical penetrance in dystonia mutation carriers, and the reversibility of disease-related functional abnormalities by treatment.
Topics: Animals; Deep Brain Stimulation; Dystonic Disorders; Humans; Molecular Chaperones; Neural Pathways; Receptors, Dopamine D2
PubMed: 19162138
DOI: 10.1016/j.neuroscience.2008.12.041 -
Human Mutation Nov 2011By family-based screening, first Fuchs and then many other authors showed that mutations in THAP1 (THAP [thanatos-associated protein] domain-containing,... (Review)
Review
By family-based screening, first Fuchs and then many other authors showed that mutations in THAP1 (THAP [thanatos-associated protein] domain-containing, apoptosis-associated protein 1) account for a substantial proportion of familial, early-onset, nonfocal, primary dystonia cases (DYT6 dystonia). THAP1 is the first transcriptional factor involved in primary dystonia and the hypothesis of a transcriptional deregulation, which was primarily proposed for the X-linked dystonia-parkinsonism (DYT3 dystonia), provided thus a new way to investigate the possible mechanism underlying the development of dystonic movements. Currently, 56 families present with a THAP1 mutation; however, no genotype/phenotype relationship has been found. Therefore, we carried out a systematic review of the literature on the THAP1 gene to colligate all reported patients with a specific THAP1 mutation and the associated clinical signs in order to describe the broad phenotypic continuum of this disorder. To facilitate the comparison of the identified mutations, we created a Locus-Specific Database (UMD-THAP1 LSDB) available at http://www.umd.be/THAP1/. Currently, the database lists 56 probands and 43 relatives with the associated clinical phenotype when available. The identification of a larger number of THAP1 mutations and collection of high-quality clinical information for each described mutation through international collaborative effort will help investigating the structure-function and genotype-phenotype correlations in DYT6 dystonia.
Topics: Adolescent; Adult; Apoptosis Regulatory Proteins; Child; Child, Preschool; DNA Mutational Analysis; DNA-Binding Proteins; Databases, Genetic; Dystonia Musculorum Deformans; Female; Genetic Association Studies; Humans; Male; Mutation; Nuclear Proteins; Young Adult
PubMed: 21793105
DOI: 10.1002/humu.21564 -
Journal of Neurology, Neurosurgery, and... Mar 1985An Australian family group is described where at least twenty members have inherited torsion dystonia and two siblings with an affected mother have similar clinical...
An Australian family group is described where at least twenty members have inherited torsion dystonia and two siblings with an affected mother have similar clinical manifestations, but have also the biochemical and pathological changes found in Wilson's disease. Whispering dysphonia was the commonest presenting symptom, and a diagnosis of hysteria was invariably made if the family history was not known. This group emphasises the enormously varied ways in which torsion dystonia may be manifested in one family, and raises the possibility of a disturbance in copper transport in diseases of the basal ganglia other than Wilson's disease.
Topics: Adolescent; Adult; Australia; Bulbar Palsy, Progressive; Child; Dystonia Musculorum Deformans; Female; Follow-Up Studies; Hepatolenticular Degeneration; Humans; Huntington Disease; Intellectual Disability; Male; Pedigree; Torticollis; Voice Disorders
PubMed: 3156966
DOI: 10.1136/jnnp.48.3.218 -
BMJ Case Reports Jul 2016Primary torsion dystonia is a movement disorder characterised by sustained or intermittent involuntary muscle contractions causing abnormal movements, postures or both....
Primary torsion dystonia is a movement disorder characterised by sustained or intermittent involuntary muscle contractions causing abnormal movements, postures or both. In this study, 3 brothers affected by inherited primary dystonia 16 (DYT16) began an oral therapy with high-dose thiamine from November to December 2015. After 3 months, an important improvement of the motor symptoms was observed. Our results support the hypothesis that pathogenesis of the symptoms might be related to a dysfunction in mitochondrial oxidative phosphorylation due to a focal impairment of thiamine-dependent processes. Our results support some authors' hypothesis that dystonia might have a mitochondrial aetiology.
Topics: Adult; Dystonic Disorders; Humans; Male; Siblings; Thiamine; Treatment Outcome; Vitamin B Complex
PubMed: 27448549
DOI: 10.1136/bcr-2016-216721 -
Molecular Therapy : the Journal of the... Jul 2023X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a retrotransposon insertion in intron 32 of the TAF1 gene. This insertion causes...
X-linked dystonia-parkinsonism (XDP) is a neurodegenerative disease caused by a retrotransposon insertion in intron 32 of the TAF1 gene. This insertion causes mis-splicing of intron 32 (TAF1-32i) and reduced TAF1 levels. TAF1-32i transcript is unique to XDP patient cells and can be detected in their extracellular vesicles (EVs). We engrafted patient and control iPSC-derived neural progenitor cells (hNPCs) into the striatum of mice. To track TAF1-32i transcript spread by EVs, we transduced the brain-implanted hNPCs with a lentiviral construct called ENoMi, which consists of a re-engineered tetraspanin scaffold tagged with bioluminescent and fluorescent reporter proteins under an EF-1α promoter. Alongside this improved detection in ENoMi-hNPCs-derived EVs, their surface allows specific immunocapture purification, thereby facilitating TAF1-32i analysis. Using this ENoMi-labeling method, TAF1-32i was demonstrated in EVs released from XDP hNPCs implanted in mouse brains. Post-implantation of ENoMi-XDP hNPCs, TAF1-32i transcript was retrieved in EVs isolated from mouse brain and blood, and levels increased over time in plasma. We compared and combined our EV isolation technique to analyze XDP-derived TAF1-32i with other techniques, including size exclusion chromatography and Exodisc. Overall, our study demonstrates the successful engraftment of XDP patient-derived hNPCs in mice as a tool for monitoring disease markers with EVs.
Topics: Humans; Mice; Animals; Neurodegenerative Diseases; Transcription Factor TFIID; Biomarkers; Brain; Extracellular Vesicles
PubMed: 37198883
DOI: 10.1016/j.ymthe.2023.05.011 -
Molecular Cell Jun 2021The Shieldin complex shields double-strand DNA breaks (DSBs) from nucleolytic resection. Curiously, the penultimate Shieldin component, SHLD1, is one of the least...
The Shieldin complex shields double-strand DNA breaks (DSBs) from nucleolytic resection. 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, thereby ensuring a proper balance between end protection and resection during DSB repair. The loss of THAP1-dependent SHLD1 expression confers cross-resistance to poly (ADP-ribose) polymerase (PARP) inhibitor and cisplatin in BRCA1-deficient cells and shorter progression-free survival in ovarian cancer patients. Moreover, the embryonic lethality and PARPi sensitivity of BRCA1-deficient mice is rescued by ablation of SHLD1. Our study uncovers a transcriptional network that directly controls DSB repair choice and suggests a potential link between DNA damage and pathogenic THAP1 mutations, found in patients with the neurodevelopmental movement disorder adult-onset torsion dystonia type 6.
Topics: Animals; BRCA1 Protein; Cell Cycle Proteins; DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; DNA-Binding Proteins; Dystonia; Female; Host Cell Factor C1; Mad2 Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Recombinational DNA Repair; Telomere-Binding Proteins; Tumor Suppressor p53-Binding Protein 1; YY1 Transcription Factor
PubMed: 33857404
DOI: 10.1016/j.molcel.2021.03.034 -
Journal of Neurology, Neurosurgery, and... Jun 1989Some patients with dystonic movements and postures not known to be caused by environmental or degenerative disorders can be segregated from classical-appearing... (Review)
Review
Some patients with dystonic movements and postures not known to be caused by environmental or degenerative disorders can be segregated from classical-appearing idiopathic torsion dystonia on the basis of distinctive clinical and pharmacologic features. Many of them should be considered within the family of dystonia, as clinical variants of idiopathic torsion dystonia, while others are better classified as being part of other families of dyskinesias. In the former group are paradoxical dystonia, myoclonic dystonia, diurnal dystonia, and dopa-responsive dystonia. The latter group consists of dystonic tics and the various entities comprising paroxysmal dystonia, namely kinesigenic, nonkinesigenic and hypnogenic dystonia.
Topics: Diagnosis, Differential; Dystonia Musculorum Deformans; Humans
PubMed: 2666583
DOI: 10.1136/jnnp.52.suppl.96 -
Movement Disorders : Official Journal... May 2022The neuronal protein alpha-synuclein (α-Syn) is crucially involved in Parkinson's disease pathophysiology. Intriguingly, torsinA (TA), the protein causative of DYT1...
BACKGROUND
The neuronal protein alpha-synuclein (α-Syn) is crucially involved in Parkinson's disease pathophysiology. Intriguingly, torsinA (TA), the protein causative of DYT1 dystonia, has been found to accumulate in Lewy bodies and to interact with α-Syn. Both proteins act as molecular chaperones and control synaptic machinery. Despite such evidence, the role of α-Syn in dystonia has never been investigated.
OBJECTIVE
We explored whether α-Syn and N-ethylmaleimide sensitive fusion attachment protein receptor proteins (SNAREs), that are known to be modulated by α-Syn, may be involved in DYT1 dystonia synaptic dysfunction.
METHODS
We used electrophysiological and biochemical techniques to study synaptic alterations in the dorsal striatum of the Tor1a / mouse model of DYT1 dystonia.
RESULTS
In the Tor1a DYT1 mutant mice, we found a significant reduction of α-Syn levels in whole striata, mainly involving glutamatergic corticostriatal terminals. Strikingly, the striatal levels of the vesicular SNARE VAMP-2, a direct α-Syn interactor, and of the transmembrane SNARE synaptosome-associated protein 23 (SNAP-23), that promotes glutamate synaptic vesicles release, were markedly decreased in mutant mice. Moreover, we detected an impairment of miniature glutamatergic postsynaptic currents (mEPSCs) recorded from striatal spiny neurons, in parallel with a decreased asynchronous release obtained by measuring quantal EPSCs (qEPSCs), which highlight a robust alteration in release probability. Finally, we also observed a significant reduction of TA striatal expression in α-Syn null mice.
CONCLUSIONS
Our data demonstrate an unprecedented relationship between TA and α-Syn, and reveal that α-Syn and SNAREs alterations characterize the synaptic dysfunction underlying DYT1 dystonia. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
Topics: Animals; Corpus Striatum; Disease Models, Animal; Dystonia; Dystonia Musculorum Deformans; Dystonic Disorders; Humans; Mice; Mice, Transgenic; Molecular Chaperones; SNARE Proteins; alpha-Synuclein
PubMed: 35420219
DOI: 10.1002/mds.29024