Pathogenesis Of Dystonia Research Articles

The Morbid Impact of Environmental Toxins on the Human Nervous System: Dystonia Nexus with Organic Solvents, Pesticides, and Heavy Metals

Dystonia is a neurological disorder characterized by involuntary muscle contractions that lead to abnormal movements and postures. This review examines environmental toxins and their etiology and pathogenesis of dystonia. Environmental toxins – organic solvents, pesticides, and heavy metals – disrupt neural pathways and neurotransmitter functions, contributing to the development of dystonia. These toxins induce neurotoxicity through mechanisms involving oxidative stress, inflammatory responses, and interference with neurotransmitter synthesis and release. Organic solvents disrupt neuronal membrane integrity and neurotransmission, while pesticides impair neurotransmitter synthesis and receptor function. Heavy metals alter ion channel function, promote oxidative stress, and trigger inflammatory responses, causing neuronal damage. Diagnosing dystonia requires a thorough medical history, neurological examination, lab work, and specialized tests, including imaging and genetic testing. Treatment strategies focus on symptom management by identifying and eliminating the source of environmental toxin exposure and medications (e.g., dopaminergic agents, anticholinergics, GABAergic agents, and BOTOX injections). These strategies are complemented by physical therapy, nutritional support, regulating monitoring and follow-up, and education and counseling.

Whole-exome sequencing in a cohort of Chinese patients with isolated cervical dystonia

BackgroundDystonia is a kind of movement disorder but its pathophysiological mechanisms are still largely unknown. Recent evidence reveals that genetical defects may play important roles in the pathogenesis of dystonia. Objectives and Methods-To explore possible causative genes in Chinese dystonia patients, DNA samples from 42 sporadic patients with isolated cervical dystonia were subjected to whole-exome sequencing. Rare deleterious variants associated with dystonia phenotype were screened out and then classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Phenolyzer was used for analyzing the most probable candidates correlated with dystonia phenotype, and SWISS-MODEL server was for predicting the 3D structures of variant proteins. ResultsAmong 42 patients (17 male and 25 female) recruited, a total of 36 potentially deleterious variants of dystonia-associated genes were found in 30 patients (30/42, 71.4 %). Four disease-causing variants including a pathogenic variant in PLA2G6 (c.797G > C) and three likely pathogenic variants in DCTN1 (c.73C > T), SPR (c.1A > C) and TH (c.56C > G) were found in four patients separately. Other 32 variants were classified as uncertain significance in 26 patients. Phenolyzer prioritized genes TH, PLA2G6 and DCTN1 as the most probable candidates correlated with dystonia phenotype. Although 3D prediction of DCTN1 and PLA2G6 variant proteins detected no obvious structural alterations, the mutation in DCTN1 (c.73C > T:p.Arg25Trp) was closely adjacent to its key functional domain. ConclusionOur whole-exome sequencing results identified a novel variant in DCTN1 in sporadic Chinese patients with isolated cervical dystonia, which however, needs our further study on its exact role in dystonia pathogenesis.

Genetics and Pathogenesis of Dystonia.

Dystonia is a clinically and genetically highly heterogeneous neurological disorder characterized by abnormal movements and postures caused by involuntary sustained or intermittent muscle contractions. A number of groundbreaking genetic and molecular insights have recently been gained. While they enable genetic testing and counseling, their translation into new therapies is still limited. However, we are beginning to understand shared pathophysiological pathways and molecular mechanisms. It has become clear that dystonia results from a dysfunctional network involving the basal ganglia, cerebellum, thalamus, and cortex. On the molecular level, more than a handful of, often intertwined, pathways have been linked to pathogenic variants in dystonia genes, including gene transcription during neurodevelopment (e.g., KMT2B, THAP1), calcium homeostasis (e.g., ANO3, HPCA), striatal dopamine signaling (e.g., GNAL), endoplasmic reticulum stress response (e.g., EIF2AK2, PRKRA, TOR1A), autophagy (e.g., VPS16), and others. Thus, different forms of dystonia can be molecularly grouped, which may facilitate treatment development in the future.

The role of protein kinase R in dystonia

Dystonia is a progressive neurological motor disease with few treatment options and no cure. This review synthesizes the results of recent studies that implicate protein kinase R in mediating the molecular mechanisms of dystonia pathogenesis. Mutations in the PKR gene EIF2AK2 and the PKR activator protein PACT are associated with early-onset generalized dystonia. Protein kinase R (PKR) is important for neuronal function. Genetic depletion or inhibition of PKR is associated with increased long-term potentiation and memory, while also causing neuronal hyper-excitability and seizures in mouse models. PKR also senses double stranded RNA within cells and activates the integrated stress response (ISR). The ISR is a conserved signaling pathway that hinges on controlled translational suppression to remodel gene expression during stress. When PKR is activated through binding double stranded RNA or the PKR activator protein PACT, PKR dimerizes, autophosphorylates, and phosphorylates the translation initiation factor eIF2. Translation suppression by p-eIF2 causes stress granule formation and the upregulation of stress-induced genes. The ISR is thought to drive cellular resilience during acute stress. However, chronic ISR activation is associated with neurological diseases, traumatic brain injury, and aging. Neurodevelopmental and neurodegenerative diseases are associated with mutations in other integrated stress response genes, suggesting a critical role for ISR regulation in neuronal health. A growing body of work suggests the ISR is also dysfunctional in dystonia. Future research investigating the molecular mechanisms of the ISR in dystonia will likely reveal therapeutic targets and treatment strategies for this currently incurable disease.

Proprioceptive Modulation of Pallidal Physiology in Cervical Dystonia.

There is a growing body of evidence suggesting that botulinum toxin can alter proprioceptive feedback and modulate the muscle-spindle output for the treatment of dystonia. However, the mechanism for this modulation remains unclear. We conducted a study involving 17 patients with cervical dystonia (CD), seven of whom had prominent CD and 10 with generalized dystonia (GD) along with CD. We investigated the effects of neck vibration, a form of proprioceptive modulation, on spontaneous single-neuron responses and local field potentials (LFPs) recorded from the globus pallidum externus (GPe) and internus (GPi). Our findings demonstrated that neck vibration notably increased the regularity of neck-sensitive GPi neurons in focal CD patients. Additionally, in patients with GD and CD, the vibration enhanced the firing regularity of non-neck-sensitive neurons. These effects on single-unit activity were also mirrored in ensemble responses measured through LFPs. Notably, the LFP modulation was particularly pronounced in areas populated with burst neurons compared to pause or tonic cells. The results from our study emphasize the significance of burst neurons in the pathogenesis of dystonia and in the efficacy of proprioceptive modulation for its treatment. Moreover, we observed that the effects of vibration on focal CD were prominent in the α band LFP, indicating modulation of pallido-cerebellar connectivity. Moreover, the pallidal effects of vibration in GD with CD involved modulation of cerebro-pallidal θ band connectivity. Our analysis provides insight into how vibration-induced changes in pallidal activity are integrated into the downstream motor circuit. © 2023 International Parkinson and Movement Disorder Society.

Spinal dystonia and other spinal movement disorders

While traditionally considered a disorder of the basal ganglia, brainstem, and cerebellum, multiple reports have shown that spinal cord pathologies may lead to dystonia. In this article, we first discuss various spinal movement disorders and the differences between tonic spasms, spinal dystonia, spinal myoclonus, spinal tremors, and paroxysmal dyskinesia. We review potential pathogenesis of spinal dystonia. We then focus on reports of dystonia secondary to spinal cord demyelinating diseases such as multiple sclerosis and neuromyelitis optica spectrum disorders. We conclude by discussing the potential treatment options for spinal dystonia.

DYT-TOR1A dystonia: an update on pathogenesis and treatment.

DYT-TOR1A dystonia is a neurological disorder characterized by involuntary muscle contractions and abnormal movements. It is a severe genetic form of dystonia caused by mutations in the TOR1A gene. TorsinA is a member of the AAA + family of adenosine triphosphatases (ATPases) involved in a variety of cellular functions, including protein folding, lipid metabolism, cytoskeletal organization, and nucleocytoskeletal coupling. Almost all patients with TOR1A-related dystonia harbor the same mutation, an in-frame GAG deletion (ΔGAG) in the last of its 5 exons. This recurrent variant results in the deletion of one of two tandem glutamic acid residues (i.e., E302/303) in a protein named torsinA [torsinA(△E)]. Although the mutation is hereditary, not all carriers will develop DYT-TOR1A dystonia, indicating the involvement of other factors in the disease process. The current understanding of the pathophysiology of DYT-TOR1A dystonia involves multiple factors, including abnormal protein folding, signaling between neurons and glial cells, and dysfunction of the protein quality control system. As there are currently no curative treatments for DYT-TOR1A dystonia, progress in research provides insight into its pathogenesis, leading to potential therapeutic and preventative strategies. This review summarizes the latest research advances in the pathogenesis, diagnosis, and treatment of DYT-TOR1A dystonia.

Dystonia is Associated with Macro and Microstructural Abnormalities of the Cerebellum: Analysis of Volumetric and Diffusion-Weighted MRI Data in the UK Biobank (P11-11.004)

<h3>Objective:</h3> To determine whether subjects with dystonia in the UK Biobank exhibit MRI-based cerebellar pathology. <h3>Background:</h3> Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and/or postures. Although classically considered a basal-ganglia disorder, neuroimaging studies of dystonia have revealed physiologic, structural, and functional changes in both the (1) pallido-thalamic and (2) cerebello-thalamic networks. Diffusion-weighted-MRI (DWI) analyses of both networks in dystonia have revealed differences in non-specific Diffusion-Tensor metrics such as Fractional Anisotropy. However newer DWI models, such as Neurite Orientation Dispersion and Density Imaging (NODDI), assess more specific and biologically relevant white-matter properties. <h3>Design/Methods:</h3> Using the UK Biobank, 23 subjects with isolated dystonia and diffusion-MRI data were identified, along with 69 control subjects without neurologic (ICD10 G-coded) diagnoses, matched (1:3) on age, sex, imaging site, and medical comorbidities relevant to white-matter integrity (hypertension, hyperlipidemia, and diabetes). Two DTI metrics (mean diffusivity and fractional anisotropy) and three NODDI metrics (intracellular volume fraction, isotropic volume fraction, and orientation dispersion) were extracted from each of four tracts (inferior, middle, and superior cerebellar peduncles, and superior thalamic radiations). Volumetric data consisted of cerebellar (15 regions), basal ganglia (3 regions), and whole-brain grey and white-matter volumes. <h3>Results:</h3> After correcting for multiple-comparisons (40 volumetric and 35 diffusion-related) using the Benjamini-Hochberg procedure (FDR = 0.05), intracellular-volume-fraction (ICVF) of the middle- and superior-cerebellar peduncles was significantly lower in subjects with dystonia, suggesting reduced axon density; volumetric analysis showed significantly reduced volumes of the motor cerebellum (lobules VI and VIII). There were no differences in basal ganglia, cortical, or whole-brain volumes. <h3>Conclusions:</h3> These findings support the hypothesis that abnormalities of cerebellar networks contribute to the pathogenesis of dystonia. <b>Disclosure:</b> Dr. Mason has nothing to disclose. Miss Haddad has nothing to disclose. The institution of Neda Jahanshad has received research support from Biogen Inc.

A novel compound heterozygous mutation of COL6A3 in Chinese patients with isolated cervical dystonia.

The etiology and pathogenesis of idiopathic dystonia remain obscure. Recent studies revealed that compound heterozygous mutations in collagen type VI alpha-3 gene COL6A3 may cause recessive isolated dystonia (DYT)-27. However, whether COL6A3 mutations are associated with Chinese patients with isolated dystonia is not yet reported. In this study, 45 Chinese patients with isolated cervical dystonia were recruited, and their blood DNA samples were subjected to whole-exome sequencing. The potential causal variants of COL6A3 were identified based on the criteria of the American College of Medical Genetics and Genomics and by prediction software. Among 45 isolated cervical dystonia patients, 18 patients (10 female patients and eight male patients) were found to have seven potential causal variants in the COL6A3 gene. Among these variants, a compound heterozygous mutation was found in one patient. One allele had a c.1264G>A mutation in exon 4 that resulted in an amino acid substitution of methionine for valine at codon 422 (p.Val422Met) and the other a c.8965+9G>A mutation involving a splicing change in exon 40. In addition, other five missense variants, including c.958G>A (p.Ala320Thr), c.1478T>C (p.Val493Ala), c.1597C>T (p.Arg533Cys), c.1762G>A (p.Asp588Asn), and c.4912G>A (p.Ala1638Thr), were identified as well. We identified a novel deleterious compound heterozygous mutation as well as five missense variants in the COL6A3 gene of Chinese patients with cervical dystonia. These findings may expand the spectrum of the COL6A3 genotype in isolated dystonia.

DYT-TOR1A genotype alters extracellular vesicle composition in murine cell model and shows potential for biomarker discovery

Introduction: Biomarkers that can be used to identify patient subgroups with shared pathophysiology and/or that can be used as pharmacodynamic readouts of disease state are valuable assets for successful clinical trial design. In translational research for brain diseases, extracellular vesicles (EVs) have become a high-priority target for biomarker discovery because of their ubiquity in peripheral biofluids and potential to indicate brain state.Materials and methods: Here, we applied unbiased quantitative proteomics of EVs isolated from DYT-TOR1A knockin mouse embryonic fibroblasts and littermate controls to discover candidates for protein biomarkers. We further examined the response of genotype perturbations to drug treatment conditions to determine their pharmacodynamic properties.Results: We found that many DYT-TOR1A MEF EV differences were significantly corrected by ritonavir, a drug recently shown to correct DYT-TOR1A phenotypes in cell and mouse disease models. We also used tool compounds to explore the effect of the integrated stress response (ISR), which regulates protein synthesis and is implicated in dystonia pathogenesis. Integrated stress response inhibition in WT cells partially phenocopied the effects of DYT-TOR1A on EV proteome composition, and ISR potentiation in DYT-TOR1A caused changes that paralleled ritonavir treatment.Conclusion: These results collectively show that DYT-TOR1A genotype alters EV protein composition, and these changes can be dynamically modulated by a candidate therapeutic drug and ISR activity state. These mouse model findings provide proof-of-concept that EVs may be a useful source of biomarkers in human populations and further suggest specific homologs to evaluate in cross-species validation.

Dystonia genes and their biological pathways.

High-throughput sequencing has been instrumental in uncovering the spectrum of pathogenic genetic alterations that contribute to the etiology of dystonia. Despite the immense heterogeneity in monogenic causes, studies performed during the past few years have highlighted that many rare deleterious variants associated with dystonic presentations affect genes that have roles in certain conserved pathways in neural physiology. These various gene mutations that appear to converge towards the disruption of interconnected cellular networks were shown to produce a wide range of different dystonic disease phenotypes, including isolated and combined dystonias as well as numerous clinically complex, often neurodevelopmental disorder-related conditions that can manifest with dystonic features in the context of multisystem disturbances. In this chapter, we summarize the manifold dystonia-gene relationships based on their association with a discrete number of unifying pathophysiological mechanisms and molecular cascade abnormalities. The themes on which we focus comprise dopamine signaling, heavy metal accumulation and calcifications in the brain, nuclear envelope function and stress response, gene transcription control, energy homeostasis, lysosomal trafficking, calcium and ion channel-mediated signaling, synaptic transmission beyond dopamine pathways, extra- and intracellular structural organization, and protein synthesis and degradation. Enhancing knowledge about the concept of shared etiological pathways in the pathogenesis of dystonia will motivate clinicians and researchers to find more efficacious treatments that allow to reverse pathologies in patient-specific core molecular networks and connected multipathway loops.

Этиологические и патогенетические механизмы формирования мышечных дистоний

This article discusses the issues of muscular dystonia pathogenesis that are relevant to modern medicine, as well as the possibility of using the pathogenetic concept as a substrate to supplement the classification criteria. Reviewing the international publications on etiopathophysiology, genetics and classification, the article summarizes the main mechanisms for the occurrence of a pathological process at different levels of the nervous system. Despite the frequent clinical similarity of the symptoms of various forms of muscular dystonia, these symptoms may be the result of dysfunction of completely different genetic and neurophysiological mechanisms. The article focuses on the importance of studying the etiological and pathogenetic mechanisms and their further implementation in clinical practice in order to develop more accurate treatment techniques aimed at eliminating the specific causes of the development of specific forms of muscular dystonia.

Chapter 21 - Isolated and combined dystonias: Update

Dystonia is a hyperkinetic movement disorder with a unique motor phenomenology that can manifest as an isolated clinical syndrome or combined with other neurological features. This chapter reviews the characteristic features of dystonia phenomenology and the syndromic approach to evaluating the disorders that may allow us to differentiate the isolated and combined syndromes. We also present the most common types of isolated and combined dystonia syndromes. Since accelerated gene discoveries have increased our understanding of the molecular mechanisms of dystonia pathogenesis, we also present isolated and combined dystonia syndromes by shared biological pathways. Examples of these converging mechanisms of the isolated and combined dystonia syndromes include (1) disruption of the integrated response pathway through eukaryotic initiation factor 2 alpha signaling, (2) disease of dopaminergic signaling, (3) alterations in the cerebello-thalamic pathway, and (4) disease of protein mislocalization and stability. The discoveries that isolated and combined dystonia syndromes converge in shared biological pathways will aid in the development of clinical trials and therapeutic strategies targeting these convergent molecular pathways.

Nuclear Pore Complex Dysfunction in Dystonia Pathogenesis: Nucleoporins in the Spotlight.

Nuclear Pore Complex Dysfunction in Dystonia Pathogenesis: Nucleoporins in the Spotlight.

Motor deficit and lack of overt dystonia in Dlx conditional Dyt1 knockout mice

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.

Increased movement-related signals in both basal ganglia and cerebellar output pathways in two children with dystonia.

The contribution of different brain regions to movement abnormalities in children with dystonia is unknown. Three awake subjects undergoing depth electrode implantation for assessments of potential deep brain recording targets performed a rhythmic figure-8 drawing task. Two subjects had dystonia, one was undergoing testing for treatment of Tourette Syndrome and had neither dystonia nor abnormal movements during testing. Movement-related signals were evaluated by determining the magnitude of task-related frequency components. Brain signals were recorded in globus pallidus internus (GPi), the ventral oralis anterior/posterior (VoaVop) and the ventral intermediate (Vim) nuclei of the thalamus. In comparison to the subject without dystonia, both children with dystonia showed increased task-related activity in GPi and Vim. This finding is consistent with a role of both basal ganglia and cerebellar outputs in the pathogenesis of dystonia. Our results further suggest that frequency analysis of brain recordings during cyclic movements may be a useful tool for analysis of the presence of movement-related signals in various brain regions.

A dual dopaminergic therapy with L-3,4-dihydroxyphenylalanine and chlorpromazine for the treatment of blepharospasm, a focal dystonia: Possible implications for striosomal D1 signaling

Impairment of balanced activity between dopamine D1 and D2 receptor functions in the striatum, particularly in striatal functional subdivisions (i.e., striosome and matrix compartments), has been proposed to underlie dystonia genesis. This study was undertaken to examine the therapeutic effect of dual dopaminergic modulation with L-3,4-dihydroxyphenylalanine (L-DOPA) and chlorpromazine (CPZ) in patients with blepharospasm, a focal dystonia. For this purpose, Dopacol tablets™ (L-DOPA 50 mg plus carbidopa 5 mg) and Wintermin™ (CPZ phenolphthalinate 180 mg/g) were used. Clinical evaluations were performed before and after an 8-week drug treatment interval using the Visual Analog Scale (VAS), Blepharospasm Disability Index (BSDI), modified VAS (mVAS), and Jankovic Rating Scale (JRS). The data were analyzed using non-parametric statistics. Results showed that in patients (n = 7) with blepharospasm, dystonia symptoms were significantly alleviated by the administration of both Dopacol tablets™ (one tablet × 3/day) and CPZ (5 mg × 3/day), as determined using the VAS, BSDI, mVAS, and JRS. In contrast, there was no improvement of dystonia symptoms in patients (n = 7) who ingested Dopacol tablets™ (one tablet × 3/day) alone, nor in those (n = 7) who ingested CPZ (5 mg × 3/day) alone. Thus, dual pharmacotherapy with L-DOPA and CPZ can exert a therapeutic effect on blepharospasm, suggesting that dystonia symptoms can be attenuated through dopaminergic modulation with inducing an increase in striatal D1-signals. Since dopamine D1 receptors are heavily enriched in the striosome compartment in the “human” striatum, our results also suggest that striosomal loss of D1-signaling may be important in the pathogenesis of dystonia.

Cerebellar Dysfunction as a Source of Dystonic Phenotypes in Mice

There is now a substantial amount of compelling evidence demonstrating that the cerebellum may be a central locus in dystonia pathogenesis. Studies using spontaneous genetic mutations in rats and mice, engineered genetic alleles in mice, shRNA knockdown in mice, and conditional genetic silencing of fast neurotransmission in mice have all uncovered a common set of behavioral and electrophysiological defects that point to cerebellar cortical and cerebellar nuclei dysfunction as a source of dystonic phenotypes. Here, we revisit the Ptf1aCre/+;Vglut2flox/flox mutant mouse to define fundamental phenotypes and measures that are valuable for testing the cellular, circuit, and behavioral mechanisms that drive dystonia. In this model, excitatory neurotransmission from climbing fibers is genetically eliminated and, as a consequence, Purkinje cell and cerebellar nuclei firing are altered in vivo, with a prominent and lasting irregular burst pattern of spike activity in cerebellar nuclei neurons. The resulting impact on behavior is that the mice have developmental abnormalities, including twisting of the limbs and torso. These behaviors continue into adulthood along with a tremor, which can be measured with a tremor monitor or EMG. Importantly, expression of dystonic behavior is reduced upon cerebellar-targeted deep brain stimulation. The presence of specific combinations of disease-like features and therapeutic responses could reveal the causative mechanisms of different types of dystonia and related conditions. Ultimately, an emerging theme places cerebellar dysfunction at the center of a broader dystonia brain network.

Harnessing Transcriptomics to Decipher Dystonia Pathogenesis.

Harnessing Transcriptomics to Decipher Dystonia Pathogenesis.

DYT6 mutated THAP1 is a cell type dependent regulator of the SP1 family

DYT6 dystonia is caused by mutations in the transcription factor THAP1. THAP1 knock-out or knock-in mouse models revealed complex gene expression changes, which are potentially responsible for the pathogenesis of DYT6 dystonia. However, how THAP1 mutations lead to these gene expression alterations and whether the gene expression changes are also reflected in the brain of THAP1 patients are still unclear. In this study we used epigenetic and transcriptomic approaches combined with multiple model systems [THAP1 patients' frontal cortex, THAP1 patients' induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons, THAP1 heterozygous knock-out rat model, and THAP1 heterozygous knock-out SH-SY5Y cell lines] to uncover a novel function of THAP1 and the potential pathogenesis of DYT6 dystonia. We observed that THAP1 targeted only a minority of differentially expressed genes caused by its mutation. THAP1 mutations lead to dysregulation of genes mainly through regulation of SP1 family members, SP1 and SP4, in a cell type dependent manner. Comparing global differentially expressed genes detected in THAP1 patients' iPSC-derived midbrain dopaminergic neurons and THAP1 heterozygous knock-out rat striatum, we observed many common dysregulated genes and 61 of them were involved in dystonic syndrome-related pathways, like synaptic transmission, nervous system development, and locomotor behaviour. Further behavioural and electrophysiological studies confirmed the involvement of these pathways in THAP1 knock-out rats. Taken together, our study characterized the function of THAP1 and contributes to the understanding of the pathogenesis of primary dystonia in humans and rats. As SP1 family members were dysregulated in some neurodegenerative diseases, our data may link THAP1 dystonia to multiple neurological diseases and may thus provide common treatment targets.