Early-onset Dystonia Research Articles

THAP1/DYT6 sequence variants in non-DYT1 early-onset primary dystonia in China and their effects on RNA expression

Mutations in the THAP1 gene were recently identified as the cause of DYT6 primary dystonia. More than 40 mutations in this gene have been described in different populations. However, no previous report has identified sequence variations that affect the transcript process of the THAP1 gene. In addition, the mutation frequency in Chinese early-onset primary dystonia has not been well characterized. One hundred and two unrelated patients with non-DYT1 early-onset primary dystonia (age at onset <26 years), family members of participants with mutations, and 200 neurologically normal controls were screened for THAP1 gene mutations. The effects of the identified mutations on RNA expression were analyzed using semi-quantitative real-time PCR. Seven sequence variants (c.63_66del TTTC, c.161G>T, c.224A>T, c.267G>A, c.339T>C, c.449A>C, and c.539T>C) were identified in this group of patients (6.9%). In this cohort, 15 subjects (seven unrelated patients and eight family members) were detected to have THAP1 sequence variants. Among these 15 subjects, 11 were manifested (penetrance of DYT6 was 73.3%) and seven presented with craniocervical involvement (63.6%). However, one patient manifested paroxysmal headshake, and one presented with essential hand tremor. Semi-quantitative real-time PCR indicated that a novel silent mutation (c.267G>A) decreased the expression of THAP1 in human lymphocytes. Our findings indicated that THAP1 sequence variants are not common in non-DYT1 early-onset primary dystonia in China and that the clinical manifestation may vary. One silent mutation (c.267G>A) was shown to affect THAP1 expression.

TorsinA and the TorsinA-Interacting Protein Printor Have No Impact on Endoplasmic Reticulum Stress or Protein Trafficking in Yeast

Early-onset torsion dystonia is a severe, life-long disease that leads to loss of motor control and involuntary muscle contractions. While the molecular etiology of the disease is not fully understood, a mutation in an AAA+ ATPase, torsinA, has been linked to disease onset. Previous work on torsinA has shown that it localizes to the endoplasmic reticulum, where there is evidence that it plays roles in protein trafficking, and potentially also protein folding. Given the high level of evolutionary conservation among proteins involved in these processes, the ability of human such proteins to function effectively in yeast, as well as the previous successes achieved in examining other proteins involved in complex human diseases in yeast, we hypothesized that Saccharomyces cerevisiae might represent a useful model system for studying torsinA function and the effects of its mutants. Since torsinA is proposed to function in protein homeostasis, we tested cells for their ability to respond to various stressors, using a fluorescent reporter to measure the unfolded protein response, as well as their rate of protein secretion. TorsinA did not impact these processes, even after co-expression of its recently identified interacting partner, printor. In light of these findings, we propose that yeast may lack an additional cofactor necessary for torsinA function or proteins required for essential post-translational modifications of torsinA. Alternatively, torsinA may not function in endoplasmic reticulum protein homeostasis. The strains and assays we describe may provide useful tools for identifying and investigating these possibilities and are freely available.

Static retention of the lumenal monotopic membrane protein torsinA in the endoplasmic reticulum

TorsinA is a membrane-associated enzyme in the endoplasmic reticulum (ER) lumen that is mutated in DYT1 dystonia. How it remains in the ER has been unclear. We report that a hydrophobic N-terminal domain (NTD) directs static retention of torsinA within the ER by excluding it from ER exit sites, as has been previously reported for short transmembrane domains (TMDs). We show that despite the NTD's physicochemical similarity to TMDs, it does not traverse the membrane, defining torsinA as a lumenal monotopic membrane protein and requiring a new paradigm to explain retention. ER retention and membrane association are perturbed by a subset of nonconservative mutations to the NTD, suggesting that a helical structure with defined orientation in the membrane is required. TorsinA preferentially enriches in ER sheets, as might be expected for a lumenal monotopic membrane protein. We propose that the principle of membrane-based protein sorting extends to monotopic membrane proteins, and identify other proteins including the monotopic lumenal enzyme cyclooxygenase 1 (prostaglandin H synthase 1) that share this mechanism of retention with torsinA.

DYT 6-A novel THAP1 mutation with excellent effect on pallidal DBS

DYT6 is an early-onset dystonia caused by variable mutations of the gene encoding the thanatos-associated protein (THAP1).1 It usually starts in the cranial region or on the upper extremities with subsequent generalization. It has been reported that deep brain stimulation of the internal globus pallidus (GPi-DBS) has moderate or unsatisfactory effects in these patients.2,3 We describe a novel mutation of the THAP1 gene in 2 siblings (a boy and a girl) with a rapid generalization into a life-threatening status dystonicus (SD) in the boy. Unlike in the 7 previously reported patients,2,3 in his case, we observed excellent long-term effects from bilateral GPi-DBS.

EFNS guidelines on diagnosis and treatment of primary dystonias

to provide a revised version of earlier guidelines published in 2006. primary dystonias are chronic and often disabling conditions with a widespread spectrum mainly in young people. primary dystonias are classified as pure dystonia, dystonia plus or paroxysmal dystonia syndromes. Assessment should be performed using a validated rating scale for dystonia. Genetic testing may be performed after establishing the clinical diagnosis. DYT1 testing is recommended for patients with primary dystonia with limb onset before age 30, and in those with an affected relative with early-onset dystonia. DYT6 testing is recommended in early-onset or familial cases with cranio-cervical dystonia or after exclusion of DYT1. Individuals with early-onset myoclonus should be tested for mutations in the DYT11 gene. If direct sequencing of the DYT11 gene is negative, additional gene dosage is required to improve the proportion of mutations detected. A levodopa trial is warranted in every patient with early-onset primary dystonia without an alternative diagnosis. In patients with idiopathic dystonia, neurophysiological tests can help with describing the pathophysiological mechanisms underlying the disorder. botulinum toxin (BoNT) type A is the first-line treatment for primary cranial (excluding oromandibular) or cervical dystonia; it is also effective on writing dystonia. BoNT/B is not inferior to BoNT/A in cervical dystonia. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for primary generalized or cervical dystonia, after medication or BoNT have failed. DBS is less effective in secondary dystonia. This treatment requires a specialized expertise and a multidisciplinary team.

Screening of the THAP1 gene in patients with early-onset dystonia: myoclonic jerks are part of the dystonia 6 phenotype

Mutations in the THAP1 gene are responsible for an autosomal dominant form of primary torsion dystonia 6 (DYT6) [1]. Patients with DYT6 are characterized usually by childhoodor early-adulthood-onset dystonia, affecting brachial, cervical, or cranial muscles with possible progression towards generalized dystonia [2–5]. We analyzed the three exons of the THAP1 gene by direct sequencing in 113 primary dystonia cases from France, European countries, and North Africa. Familial or isolated cases with primary dystonias with early-onset ( C/p.Ser6Pro and c.215T>G/p.Leu72Arg) which affect residues that are highly conserved across

Behavioural and pharmacological examinations in a transgenic mouse model of early-onset torsion dystonia

Early-onset torsion dystonia is an autosomal dominant movement disorder associated with the DYT1 gene (TOR1A) defect which results in a deletion of a glutamic acid residue in the protein torsinA. The pathophysiology of dystonia is poorly understood. Well characterized animal models can help to give insights into the underlying mechanisms and thereby to develop new therapeutics. In the present study, we further characterized transgenic DYT1 mice, which were initially described to exhibit “dystonia-like” postures. In the present study, several behavioural tests in untreated animals did not show strong differences between transgenic and control mice, but nearly all transgenic mice showed “dystonia-like” postures. However, these movements, also observed in control mice, have to be regarded as a clasping reflex. Since dystonia is thought to be related to dopaminergic dysfunctions, pharmacological investigations have been performed to clarify if dopaminergic substances alter motor behaviour in transgenic mice. Chronic treatment with L-DOPA (combined with carbidopa) enhanced the hindlimb claspings only in transgenic mice, while acute applications of drugs, which exert more selective effects on the dopaminergic system, caused similar reactions in transgenic mice and control mice. Therefore, these data do not provide clear evidence for dysfunctions of the dopaminergic system in this mouse model.

A Unique Redox-sensing Sensor II Motif in TorsinA Plays a Critical Role in Nucleotide and Partner Binding

Early onset dystonia is commonly associated with the deletion of one of a pair of glutamate residues (ΔE302/303) near the C terminus of torsinA, a member of the AAA+ protein family (ATPases associated with a variety of cellular activities) located in the endoplasmic reticulum lumen. The functional consequences of the disease-causing mutation, ΔE, are not currently understood. By contrast to other AAA+ proteins, torsin proteins contain two conserved cysteine residues in the C-terminal domain, one of which is located in the nucleotide sensor II motif. Depending on redox status, an ATP hydrolysis mutant of torsinA interacts with lamina-associated polypeptide 1 (LAP1) and lumenal domain like LAP1 (LULL1). Substitution of the cysteine in sensor II diminishes the redox-regulated interaction of torsinA with these substrates. Significantly, the dystonia-causing mutation, ΔE, alters the ability of torsinA to mediate the redox-regulated interactions with LAP1 and LULL1. Limited proteolysis experiments reveal redox- and mutation-dependent changes in the local conformation of torsinA as a function of nucleotide binding. These results indicate that the cysteine-containing sensor II plays a critical role in redox sensing and the nucleotide and partner binding functions of torsinA and suggest that loss of this function of torsinA contributes to the development of DYT1 dystonia.

Clinical neuroimaging and electrophysiological assessment of three DYT6 dystonia families

The purpose of the study was to delineate clinical and electrophysiological characteristics as well as laryngoscopical and transcranial ultrasound (TCS) findings in THAP1 mutation carriers (MutC). According to recent genetic studies, DYT6 (THAP1) gene mutations are an important cause of primary early-onset dystonia. In contrast to DYT1 mutations, THAP1 mutations are associated with primary early-onset segmental or generalised dystonia frequently involving the craniocervical region and the larynx. Blood samples from twelve individuals of three German families with DYT6 positive index cases were obtained to test for THAP1 mutations. Eight THAP1 MutC were identified. Of these, six (three symptomatic and three asymptomatic) THAP1 MutC could be clinically evaluated. Laryngoscopy was performed to evaluate laryngeal dysfunction in patients. Brainstem echogenicity was investigated in all MutC using TCS. Two of the patients had undergone bilateral pallidal DBS. In all three symptomatic MutC, early-onset laryngeal dystonia was a prominent feature. Laryngeal assessment demonstrated adductor-type dystonia in all of them. On clinical examination, the three asymptomatic MutC also showed subtle signs of focal or segmental dystonia. TCS revealed increased substantia nigra (SN) hyperechogenicity in all MutC. Intraoperative microelectrode recordings under general anesthesia in two of the patients showed no difference between THAP1 and previously operated DYT1 MutC. The presence of spasmodic dysphonia in patients with young-onset segmental or generalised dystonia is a hallmark of DYT6 dystonia. SN hyperechogenicity on TCS may represent an endophenotype in these patients. Pallidal DBS in two patients was unsatisfactory.

DYT6 dystonia: Mutation screening, phenotype, and response to deep brain stimulation

Mutations in THAP1, a gene encoding a nuclear pro-apoptotic protein, have been associated with DYT6 dystonia. First reports on the phenotype of DYT6 dystonia show an early onset dystonia with predominant cranio-cervical and laryngeal involvement. Here we assessed the frequency and phenotype of THAP1 mutation carriers in a large Dutch cohort of adult-onset (≥26 years) dystonia (n = 388) and early-onset dystonia (n = 67) patients. We describe the phenotype of DYT6 dystonia patients and their response on GPi DBS. Overall, 3 nonsynonymous heterozygous mutations were detected in the early-onset group (4.5%). Two DYT6 families were identified, showing a heterozygous phenotype. All patients had segmental or generalized dystonia, often associated with profound oromandibular and laryngeal involvement. No nonsynonymous mutations were found in patients with adult-onset focal dystonia. Rare synonymous variants were identified in conserved regions of THAP1, two in the adult-onset cervical dystonia group and one in the control group. Four DYT6 dystonia patients were treated with GPi DBS with moderate to good response on motor function but marginal benefit on speech.

The early-onset torsion dystonia-associated protein, torsinA, is a homeostatic regulator of endoplasmic reticulum stress response

Early-onset torsion dystonia is the most severe heritable form of dystonia, a human movement disorder that typically starts during a developmental window in early adolescence. Deletion in the DYT1 gene, encoding the torsinA protein, is responsible for this dominantly inherited disorder, which is non-degenerative and exhibits reduced penetrance among carriers. Here, we explore the hypothesis that deficits in torsinA function result in an increased vulnerability to stress associated with protein folding and processing in the endoplasmic reticulum (ER), where torsinA is located. Using an in vivo quantitative readout for the ER stress response, we evaluated the consequences of torsinA mutations in transgenic nematodes expressing variants of human torsinA. This analysis revealed that, normally, torsinA serves a protective function to maintain a homeostatic threshold against ER stress. Furthermore, we show that the buffering capacity of torsinA is greatly diminished by the DYT1-associated deletion or mutations that prevent its translocation to the ER, block ATPase activity, or increase the levels of torsinA in the nuclear envelope versus ER. Combinations of transgenic Caenorhabditis elegans designed to mimic clinically relevant genetic modifiers of disease susceptibility also exhibit a direct functional correlation to changes in the ER stress response. Furthermore, using mouse embryonic fibroblasts (MEFs) from torsinA knockout mice, we demonstrated that loss of endogenous torsinA results in enhanced sensitivity to ER stress. This study extends our understanding of molecular mechanisms underlying dystonia, and establishes a new functional paradigm to evaluate therapeutic strategies to compensate for reduced torsinA activity in the ER as a means to restore homeostatic balance and neuronal function.

The role of genes in causing dystonia

In recent years, the identification of several new dystonia genes has provided important insights into the nature of this clinically and genetically heterogeneous disorder. To identify the role of genes in the pathophysiology of dystonia. Literature review from 1985 to 2009. Early-onset dystonia is overall rare, often monogenic and tends to spread to become generalized. In contrast, adult-onset dystonia is relatively common, typically sporadic and usually remains focal. To date, 19 different forms of monogenic dystonia (primary dystonias and dystonia-plus syndromes) have been identified and classified as DYT loci. Likewise, secondary dystonia is a feature of a large number of hereditary conditions, such as Wilson disease or neuroacanthocytosis. This review focuses on the eight monogenic primary dystonias, six of which are associated with an early-onset generalized phenotype (DYT1, 2, 4, 6, 16 and 17), while the remaining two are characterized by an adolescent- or adult-onset focal or segmental form of dystonia (DYT7 and 13). Primary dystonias have a strong genetic component that is most obvious in the rare monogenic early-onset generalized forms. However, genetic risk factors also are likely to play an important role in the pathophysiology of the much more common late-onset focal and segmental primary dystonias. The identification of these genetic factors is a critical future aim in dystonia research.

Chemical enhancement of torsinA function in cell and animal models of torsion dystonia

Movement disorders represent a significant societal burden for which therapeutic options are limited and focused on treating disease symptomality. Early-onset torsion dystonia (EOTD) is one such disorder characterized by sustained and involuntary muscle contractions that frequently cause repetitive movements or abnormal postures. Transmitted in an autosomal dominant manner with reduced penetrance, EOTD is caused in most cases by the deletion of a glutamic acid (DeltaE) in the DYT1 (also known as TOR1A) gene product, torsinA. Although some patients respond well to anticholingerics, therapy is primarily limited to either neurosurgery or chemodenervation. As mutant torsinA (DeltaE) expression results in decreased torsinA function, therapeutic strategies directed toward enhancement of wild-type (WT) torsinA activity in patients who are heterozygous for mutant DYT1 may restore normal cellular functionality. Here, we report results from the first-ever screen for candidate small molecule therapeutics for EOTD, using multiple activity-based readouts for torsinA function in Caenorhabditis elegans, subsequent validation in human DYT1 patient fibroblasts, and behavioral rescue in a mouse model of DYT1 dystonia. We exploited the nematode to rapidly discern chemical effectors of torsinA and identified two classes of antibiotics, quinolones and aminopenicillins, which enhance WT torsinA activity in two separate in vivo assays. Representative molecules were assayed in EOTD patient fibroblasts for improvements in torsinA-dependent secretory function, which was improved significantly by ampicillin. Furthermore, a behavioral defect associated with an EOTD mouse knock-in model was also rescued following administration of ampicillin. These combined data indicate that specific small molecules that enhance torsinA activity represent a promising new approach toward therapeutic development for EOTD, and potentially for other diseases involving the processing of mutant proteins.

THAP1 mutations (DYT6) are an additional cause of early-onset dystonia

The clinical phenotype of DYT6 consists mainly of primary craniocervical dystonia. Recently, the THAP1 gene was identified as the cause of DYT6, where a total of 13 mutations have been identified in Amish-Mennonite and European families. We sequenced the THAP1 gene in a series of 362 British, genetically undetermined, primary dystonia patients (78 with focal, 186 with segmental, and 98 with generalized dystonia) and in 28 dystonia-manifesting DYT1 patients and 176 normal control individuals. Nine coding mutations were identified in the THAP1 gene. Two were small deletions, 2 were nonsense, and 5 were missense. Eight mutations were heterozygous, and 1 was homozygous. The main clinical presentation of cases with THAP1 mutations was early-onset (<30 years) dystonia in the craniocervical region or the limbs (8 of 9 patients). There was phenotypic variability with laryngeal or oromandibular dystonia present in 3 cases. Four of 9 THAP1 cases developed generalized dystonia. The number of THAP1 mutations has been significantly expanded, indicating an uncommon but important cause of dystonia. Coding mutations account for 9 of 362 dystonia cases, indicating a mutation frequency of 2.5% of dystonia cases in the population that we have screened. The majority of cases reported here with THAP1 mutations had craniocervical- or limb-onset segmental dystonia, but we also identified 1 homozygous THAP1 mutation, associated initially with writer's dystonia and then developing segmental dystonia. Three of our patients had a nonsense or frameshift THAP1 mutation and the clinical features of laryngeal or oromandibular dystonia. These data suggest that early-onset dystonia that includes the involvement of the larynx or face is frequently associated with THAP1 mutations.

The early-onset torsion dystonia-associated protein, torsinA, displays molecular chaperone activity in vitro.

TorsinA is a member of the AAA+ ATPase family of proteins and, notably, is the only known ATPase localized to the ER lumen. It has been suggested to act as a molecular chaperone, while a mutant form associated with early-onset torsion dystonia, a dominantly inherited movement disorder, appears to result in a net loss of function in vivo. Thus far, no studies have examined the chaperone activity of torsinA in vitro. Here we expressed and purified both wild-type (WT) and mutant torsinA fusion proteins in bacteria and examined their ability to function as molecular chaperones by monitoring suppression of luciferase and citrate synthase (CS) aggregation. We also assessed their ability to hold proteins in an intermediate state for refolding. As measured by light scattering and SDS-PAGE, both WT and mutant torsinA effectively, and similarly, suppressed protein aggregation compared to controls. This function was not further enhanced by the presence of ATP. Further, we found that while neither form of torsinA could protect CS from heat-induced inactivation, they were both able to reactivate luciferase when ATP and rabbit reticulocyte lysate were added. This suggests that torsinA holds luciferase in an intermediate state, which can then be refolded in the presence of other chaperones. These data provide conclusive evidence that torsinA acts as a molecular chaperone in vitro and suggests that early-onset torsion dystonia is likely not a consequence of a loss in torsinA chaperone activity but might be an outcome of insufficient torsinA localization at the ER to manage protein folding or trafficking.

Clinical and neurophysiological improvement of SGCE myoclonus–dystonia with GPi deep brain stimulation

Myoclonus–dystonia (M–D) is characterized by early onset myoclonus and dystonia. It is thought to be subcortical in origin. Response to oral medications may be incomplete, such that deep brain stimulation (DBS) surgery to the globus pallidum interna (GPi) or ventral intermediate thalamic nucleus (VIM) may be considered. The optimal site is not known. The physiology and surgical response for a 63-year-old woman who underwent GPi DBS for M–D with onset at age 2 and related to a mutation in the epsilon-sarcoglycan gene ( SGCE) is described. She showed excellent clinical and neurophysiological improvement of both myoclonus and dystonia, suggesting that modulation by DBS is effective even after long disease duration and only partial response to oral medications.

Mutant torsinA interacts with tyrosine hydroxylase in cultured cells

A specific mutation (ΔE302/303) in the torsinA gene underlies most cases of dominantly inherited early-onset torsion dystonia. This mutation causes the protein to aggregate and form intracellular inclusion bodies in cultured cells and animal models. Co-expression of the wildtype and mutant proteins resulted in the redistribution of the wildtype protein from the endoplasmic reticulum to inclusion bodies in cultured HEK293 cells, and this was associated with increased interaction between the two proteins. Expression of ΔE302/303 but not wildtype torsinA in primary postnatal midbrain neurons resulted in the formation of intracellular inclusion bodies, predominantly in dopaminergic neurons. Tyrosine hydroxylase was sequestered in these inclusions and this process was mediated by increased protein–protein interaction between mutant torsinA and tyrosine hydroxylase. Analysis in an inducible neuroblastoma cell culture model demonstrated altered tyrosine hydroxylase activity in the presence of the mutant but not wildtype torsinA protein. Our results suggest that the interaction of tyrosine hydroxylase and mutant torsinA may contribute to the phenotype and reported dopaminergic dysfunction in torsinA-mediated dystonia.

Prevalence of Primary Focal or Segmental Dystonia in Adults in the District of Foggia, Southern Italy: A Service-Based Study

Background: Primary focal or segmental dystonia is a rare clinical condition including early-onset dystonia, which has the tendency to generalize, and late-onset dystonia, which may be focal or segmental. The prevalence of late-onset dystonia ranges from 30 to 7,320 cases per million, but no data are available in Italy. Methods: A service-based study was conducted in the period 1 January 2001 through 31 December 2002 in the administrative district of Foggia, southern Italy (population 541,653). Cases were traced through hospital discharge diagnosis, botulinum toxin services, day hospital access, ear, nose and throat, ophthalmology and orthopedic surgery specialists, and territorial outpatient services. Inclusion criteria were age 17 years or older, residency in the study area and a diagnosis of primary focal/segmental dystonia. Results: A total of 69 patients were included, giving a crude prevalence of 127.4 per 1,000,000 (women: 146.4; men: 107.0; age 18–34 years: 39.2; 35–54 years: 98.7; 55–74 years: 273.6; 75+ years: 163.3). The standardized rate was 137.5 (95% confidence interval 107.0–174.6). Blepharospasm was the commonest clinical condition (prevalence 68.2), followed by cervical dystonia (prevalence 44.8). Conclusion: The prevalence of primary focal or segmental dystonia in Italy is in keeping with several other reports, but is lower than in studies performed in northern Europe, Minnesota, USA, and Japan. The difference in our results may be mostly explained by misdiagnosis, underascertainment of cases and a fairly limited observation period.

Mutations in THAP1 (DYT6) in early-onset dystonia: a genetic screening study

Mutations in THAP1 were recently identified as the cause of DYT6 primary dystonia; a founder mutation was detected in Amish-Mennonite families, and a different mutation was identified in another family of European descent. To assess more broadly the role of this gene, we screened for mutations in families that included one family member who had early-onset, non-focal primary dystonia. We identified 36 non-DYT1 multiplex families in which at least one person had non-focal involvement at an age of onset that was younger than 22 years. All three coding exons of THAP1 were sequenced, and the clinical features of individuals with mutations were compared with those of individuals who were negative for mutations in THAP1. Genotype-phenotype differences were also assessed. Of 36 families, nine (25%) had members with mutations in THAP1, and most were of German, Irish, or Italian ancestry. One family had the Amish-Mennonite founder mutation, whereas the other eight families each had novel, potentially truncating or missense mutations. The clinical features of the families with mutations conformed to the previously described DYT6 phenotype; however, age at onset was extended from 38 years to 49 years. Compared with non-carriers, mutation carriers were younger at onset and their dystonia was more likely to begin in brachial, rather than cervical, muscles, become generalised, and include speech involvement. Genotype-phenotype differences were not found. Mutations in THAP1 underlie a substantial proportion of early-onset primary dystonia in non-DYT1 families. The clinical features that are characteristic of affected individuals who have mutations in THAP1 include limb and cranial muscle involvement, and speech is often affected. Dystonia Medical Research Foundation; Bachmann-Strauss Dystonia and Parkinson Foundation; National Institute of Neurological Disorders and Stroke; Aaron Aronov Family Foundation.

Investigating Molecular Chaperone Activity Associated with Human TorsinA

TorsinA is a member of the AAA+ ATPase family of proteins and, interestingly, is the only such ATPase localized to the ER lumen. TorsinA has been suggested to act as a molecular chaperone while a deletion mutant form associated with early‐onset torsion dystonia, a dominantly inherited movement disorder, appears to result in a net loss‐of‐function in vivo. Thus far, no studies have examined the chaperone activity of torsinA in vitro. Here we expressed and purified both WT and mutant torsinA fusion proteins (to maltose binding protein) in bacteria and examined their ability to function as molecular chaperones by monitoring suppression of luciferase and citrate synthase aggregation, as well as luciferase reactivation. As measured by light scattering, both WT and mutant torsin effectively and similarly suppressed protein aggregation compared to controls. Further, both forms of torsinA demonstrated the capacity to hold luciferase in an intermediate state for refolding and reactivation by other chaperones. These data not only provide conclusive evidence that torsinA acts as a molecular chaperone in vitro, but also suggest that dystonia is likely not a consequence of a loss in torsinA chaperone activity.Research support: Dystonia Medical Research Foundation