DYT1 Mutation Research Articles

Disordered network structure and function in dystonia: pathological connectivity vs. adaptive responses.

Primary dystonia is thought to emerge through abnormal functional relationships between basal ganglia and cerebellar motor circuits. These interactions may differ across disease subtypes and provide a novel biomarker for diagnosis and treatment. Using a network mapping algorithm based on resting-state functional MRI (rs-fMRI), a method that is readily implemented on conventional MRI scanners, we identified similar disease topographies in hereditary dystonia associated with the DYT1 or DYT6 mutations and in sporadic patients lacking these mutations. Both networks were characterized by contributions from the basal ganglia, cerebellum, thalamus, sensorimotor areas, as well as cortical association regions. Expression levels for the two networks were elevated in hereditary and sporadic dystonia, and in non-manifesting carriers of dystonia mutations. Nonetheless, the distribution of abnormal functional connections differed across groups, as did metrics of network organization and efficiency in key modules. Despite these differences, network expression correlated with dystonia motor ratings, significantly improving the accuracy of predictions based on thalamocortical tract integrity obtained with diffusion tensor MRI (DTI). Thus, in addition to providing unique information regarding the anatomy of abnormal brain circuits, rs-fMRI functional networks may provide a widely accessible method to help in the objective evaluation of new treatments for this disorder.

DBS Treatment in a 18-Year-Old Patient with Refractory Dystonia Due to DYT1 Mutation: a case report

Welcome to BRAZILIAN JOURNAL OF NEUROSURGERY (JBNC), the official journal of the Brazilian Academy of Neurosurgery, is the oldest Neurosurgery journal in our country. It started in 1973 with the name of “Seara Médica Neurocirúrgica” and, since the beginning, it has been an extremely important information organ for Brazilian neurosurgeons. Brazil is the country with the third largest number of neurosurgeons in the world. Despite this large number of colleagues working in the specialty, we still do not have any journal indexed in PubMedTM, which is considered the most important database for medical journals in the world. Bem-vindo ao Jornal Brasileiro de Neurocirurgia - JBNC. Welcome to Brazilian Journal of Neurosurgery. O JORNAL BRASILEIRO DE NEUROCIRURGIA (JBNC), órgão oficial da Academia Brasileira de Neurocirurgia, é a revista de neurocirurgia mais antiga do nosso país. Iniciou no ano de 1973 com o nome de “Seara Médica Neurocirúrgica” e desde o início tem sido um órgão de informação de extrema importância para os neurocirurgiões brasileiros.

DBS treatment in an 18-year-old with refractory dystonia due to DYT1 mutation: a case report

Introduction: The term dystonia may be defined by abnormal involuntary movements or postures due to sustained or intermittent muscle contractions. One of the most common aetiologies of isolated dystonia is due to the mutation in DYT1 gene, resulting in a disorder of abnormal regulation of gene transcription and neuronal circuit development. Of all the patients with this mutation, about 30-40% will develop symptoms of the disease. Typically, the clinical manifestation of this type of dystonia will begin from the first to third decade of life, with generalized distribution, and involving more likely the lower limbs or, less frequently, the upper limbs and trunk. Objective: To present a case of an infrequent refractory dystonia due to DYT1 gene mutation in an 18-year-old male patient that was later treated with Deep Brain Stimulation (DBS). Case report: Here we report about the case of a 18-year-old male patient affected by torsion dystonia of the neck and a segment of the upper limbs. He first exhibited symptoms when he was 15 years old and, since then, has had a series of complications, such as severe pain and recurrent pneumonia. Genetic analysis identified a DYT1 gene superexpression mutation. Previous therapies had included physiotherapy, botulinum toxin injections, drugs such as primidone and clonazepam, but all with little improvement. Due to the patient's severe torsion dystonia on his right side, it was decided to implant a DBS only in the left internal globus pallidus (GPi) posteromedial area, in a brain surgery with general anesthesia that took place in March 2018. After 10 months, the same procedure was made in the right GPi, at the subthalamic nucleus, aiming to treat his dystonic tremors located in the left part of the body. The electrodes inserted were Medtronic® 3389 and the generator was Activa RC rechargeable, with 0.5 mm spacing. The following programming was set: current of 3 mA, frequency of 130 Hz and pulse width of 90 μs. The battery of the electrode was inserted in the right side of the chest due to the patient's more severe torsion. The post-operative (PO) was successful, without any deficit, being discharged from the hospital at the PO day 4 in the first surgery and day 2 and in the second. After a 2-year follow-up period, the patient presents a normal life compared to the average of his age, without any of the symptoms or complications he had before. He regularly attends physiotherapy and fitness centres to maintain muscle training.

CNS critical periods: implications for dystonia and other neurodevelopmental disorders.

Critical periods are discrete developmental stages when the nervous system is especially sensitive to stimuli that facilitate circuit maturation. The distinctive landscapes assumed by the developing CNS create analogous periods of susceptibility to pathogenic insults and responsiveness to therapy. Here, we review critical periods in nervous system development and disease, with an emphasis on the neurodevelopmental disorder DYT1 dystonia. We highlight clinical and laboratory observations supporting the existence of a critical period during which the DYT1 mutation is uniquely harmful, and the implications for future therapeutic development.

Epidemiology of DYT1 dystonia: Estimating prevalence via genetic ascertainment.

ObjectiveTo estimate the prevalence of TOR1A sequence variants associated with DYT1 dystonia.MethodsWe determined the frequency of the common trinucleotide deletion that causes DYT1 in the Genome Aggregation Database and the Penn Medicine Biobank, totaling exomes from over 135,000 individuals. We also evaluated the prevalence of other possible pathogenic variants in this gene and asked whether the D216H polymorphism is linked to a higher diagnostic rate for dystonia independent of the DYT1-causing mutation.ResultsThe estimated range of prevalence of the most common pathogenic variant that causes DYT1 is ∼17.6–26.1 carriers per 100,000 individuals. Based on the different data sets used, we predict that there are between 54,366 and 80,891 mutation carriers in the United States, which, due to the reduced penetrance of this variant, would translate into 16,475–24,513 DYT1 patients.ConclusionsOur data provide a prevalence estimate of the most common DYT1 mutation in the general population. This information is specifically important for those with interest in the development of precision therapeutics for dystonia.

The cognitive features of idiopathic and DYT1 dystonia.

Dystonia is a common movement disorder. In this paper, we review the literature on cognitive function in idiopathic and DYT1 dystonia. In idiopathic or DYT1 dystonia, cognition is largely intact with only isolated executive dysfunction. Dystonia patients also have increased temporal and spatial discrimination thresholds, considered endophenotypes of the disorder because deficits are also shown by unaffected relatives and nonmanifesting carriers of the DYT1 mutation. Anticholinergic medication in high doses can be associated with memory impairment in dystonia. The successful treatment of dystonia with botulinum toxin injections or deep brain stimulation does not produce any major adverse effects on cognition. The aspects of cognition that require further investigation in future studies of dystonia include inhibitory control, decision making, and social cognition. © 2017 International Parkinson and Movement Disorder Society.

Deep brain stimulation and dystonia: About 10 new pediatric cases and a new DBS center in Paris

Objective: Deep Brain Stimulation (DBS) is a surgical technique used for dystonic patients during which a continuous electrical stimulation is delivered to the Globus Pallidum. Technical improvements render this procedure possible for young children. However, predictive factors for good responders remain poorly understood. We opened a new DBS pediatric center in 2015. We present our first results and the organization of our multidisciplinary care system. Methods: We report a series of 10 children seen in consultation for DBS during 2015–2016. In the absence of radiological or etiologic contraindications, the files are reviewed and the indications for implantation are validated in multidisciplinary consultation (neuropediatricians, neurologists, neurosurgeons, rehabilitation physicians). Once included, children are evaluated pre- and post-operatively by the “dystonia referents” team within the hospital (psychologist, physiotherapist, nurse, anesthetist, resuscitator, ENT, photographer for documentation of symptoms) conjointly with the neuropediatrician and neurosurgeon. Results: 5 children were implanted (2 DYT1 mutations, 1 PKAN, 1 severe dyskinetic dystonia, 1 generalized dystonia), 3 were finally excluded and 2 refused intervention. All implanted patients improved (video), between 30 to 95% (patient DYT1). The decreased dyskinesias has also uncovered learning abilities in the dyskinetic patient. Conclusion: DBS of the GPi has a well-known efficacy in DYT1, however recent studies as ours show that other primary or secondary dystonias may benefit as well from such interventions. Implantation in young children, however, poses a problem concerning the cumbersomeness long-term follow-up and need for regular re- interventions. The indications for implantation require in our opinion a multidisciplinary decision and to obtain the perfect adhesion of the family. A protocoled and rigorous follow-up of this population will improve both the selection criteria and suggest predictive parameters for better responders.

Deep brain stimulation for myoclonus-dystonia syndrome with double mutations in DYT1 and DYT11

Myoclonus-dystonia syndrome (MDS) is a rare autosomal dominant inherited disorder characterized by the presentation of both myoclonic jerks and dystonia. Evidence is emerging that deep brain stimulation (DBS) may be a promising treatment for MDS. However, there are no studies reporting the effects of DBS on MDS with double mutations in DYT1 and DYT11. Two refractory MDS patients with double mutations were treated between 2011 and 2015 in our center. Genetic testing for DYT1 and DYT11 was performed through polymerase chain reaction amplification and direct sequencing of the specific exons of genes. For the first patient, initial bilateral ventral intermediate thalamus nucleus (Vim) DBS was performed. Because of worsening dystonia after initial improvement in symptoms, subsequent bilateral globus pallidus internus (GPi) DBS was offered at 43 months after initial surgery, which reversed the deterioration and restored the motor function. For the second patient, initial improvement in motor symptoms and quality of life was sustained at the follow-up 6 months after bilateral Vim DBS treatment. Thus, DBS may be an effective therapeutic option for MDS, even in patients with double mutations. Moreover, GPi DBS may be used as a supplementary treatment when initial Vim DBS fails to control MDS symptoms.

Functional Connectivity Networks in Asymptomatic and Symptomatic DYT1 Carriers.

DYT1 mutation is characterized by focal to generalized dystonia and incomplete penetrance. To explore the complex perturbations in the different neural networks and the mutual interactions among them, we studied symptomatic and asymptomatic DTY1 mutation carriers by resting-state functional MRI. A total of 7 symptomatic DYT1, 10 asymptomatic DYT1, and 26 healthy controls were considered. Resting-state functional MRI (Oxford Centre for Functional MRI of the Brain) [FMRIB] Software Library) (FSL) MELODIC, dual regression, (as a toolbox of FSL, with Nets is referred to "networks") (FSLNets) (http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/FSLNets) was performed on 9 resting-state neural networks. DYT1 mutation signature (symptomatic DYT1 and asymptomatic DYT1) was characterized by increased connectivity in the dorsal attention network and in the left fronto-parietal network. Functional correlates of symptomatic DYT1 patients (symptomatic DYT1 vs healthy controls) showed increased connectivity in the sensorimotor network. This study argues that DYT1 dystonia is a network disorder, with crucial nodes in sensory-motor integration of posterior parietal structures. A better characterization of cortical networks involved in dystonia is crucial for possible neurophysiological therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society.

Pallidal or Subthalamic Deep Brain Stimulation for the Generalized Dystonia Treatment

One of the most effective treatments of medically refractory generalized dystonia (GD) is pallidal deep brain stimulation (GPi DBS). For selected group of GD patients’ subthalamic deep brain stimulation (STN DBS) might be similarly effective. The authors present a group of patients diagnosed with GD, treated with GPi or STN DBS. Materials and methods: Between 2005 and 2009 eleven female and eight male patients with diagnosed GD were treated with GPi DBS or STN DBS. Mean age at implantation was 26 ± 6. Two patients were diagnosed with DYT-1 mutation. Seven patients were diagnosed with PANK-2 mutation. One patient with previous bilateral pallidotomies and six patients with diagnosed PANK-2 mutation were qualified to STN DBS. Rest of the group was qualified to GPi DBS. Clinical status of the patients was evaluated with a package of dystonia scales. The follow-up evaluation was conducted 60 months after implantation. Results: The patients reported subjective improvement following surgery that was confirmed with tailored scales. Mean improvement was evaluated with Global Dystonia Scale to 48%. More significant improvement was reported in the GPi group than in the STN group (51% vs. 38%) The best results were achieved in the DYT-1 group (89%). Conclusion: Although analyzed group is not large, the authors state that deep brain stimulation is effective and safe method of GD treatment. Decision which anatomical target is optimal should be undertaken individually depending on clinical history, phenotype and etiology of GD.

Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice.

DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinAΔE). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinAΔE does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.

TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration.

Lack of a preclinical model of primary dystonia that exhibits dystonic-like twisting movements has stymied identification of the cellular and molecular underpinnings of the disease. The classical familial form of primary dystonia is caused by the DYT1 (ΔE) mutation in TOR1A, which encodes torsinA, AAA⁺ ATPase resident in the lumen of the endoplasmic reticular/nuclear envelope. Here, we found that conditional deletion of Tor1a in the CNS (nestin-Cre Tor1a(flox/-)) or isolated CNS expression of DYT1 mutant torsinA (nestin-Cre Tor1a(flox/ΔE)) causes striking abnormal twisting movements. These animals developed perinuclear accumulation of ubiquitin and the E3 ubiquitin ligase HRD1 in discrete sensorimotor regions, followed by neurodegeneration that was substantially milder in nestin-Cre Tor1a(flox/ΔE) compared with nestin-Cre Tor1a(flox/-) animals. Similar to the neurodevelopmental onset of DYT1 dystonia in humans, the behavioral and histopathological abnormalities emerged and became fixed during CNS maturation in the murine models. Our results establish a genetic model of primary dystonia that is overtly symptomatic, and link torsinA hypofunction to neurodegeneration and abnormal twisting movements. These findings provide a cellular and molecular framework for how impaired torsinA function selectively disrupts neural circuits and raise the possibility that discrete foci of neurodegeneration may contribute to the pathogenesis of DYT1 dystonia.

TorsinA rescues ER-associated stress and locomotive defects in C. elegans models of ALS

Molecular mechanisms underlying neurodegenerative diseases converge at the interface of pathways impacting cellular stress, protein homeostasis and aging. Targeting the intrinsic capacities of neuroprotective proteins to restore neuronal function and/or attenuate degeneration represents a potential means toward therapeutic intervention. The product of the human DYT1 gene, torsinA, is a member of the functionally diverse AAA+ family of proteins and exhibits robust molecular-chaperone-like activity, both in vitro and in vivo. Although mutations in DYT1 are associated with a rare form of heritable generalized dystonia, the native function of torsinA seems to be cytoprotective in maintaining the cellular threshold to endoplasmic reticulum (ER) stress. Here we explore the potential for torsinA to serve as a buffer to attenuate the cellular consequences of misfolded-protein stress as it pertains to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The selective vulnerability of motor neurons to degeneration in ALS mouse models harboring mutations in superoxide dismutase (SOD1) has been found to correlate with regional-specific ER stress in brains. Using Caenorhabditis elegans as a system to model ER stress, we generated transgenic nematodes overexpressing either wild-type or mutant human SOD1 to evaluate their relative impact on ER stress induction in vivo. These studies revealed a mutant-SOD1-specific increase in ER stress that was further exacerbated by changes in temperature, all of which was robustly attenuated by co-expression of torsinA. Moreover, through complementary behavioral analysis, torsinA was able to restore normal neuronal function in mutant G85R SOD1 animals. Furthermore, torsinA targeted mutant SOD1 for degradation via the proteasome, representing mechanistic insight on the activity that torsinA has on aggregate-prone proteins. These results expand our understanding of proteostatic mechanisms influencing neuronal dysfunction in ALS, while simultaneously highlighting the potential for torsinA as a novel target for therapeutic development.

A CASE SUPPORTING THE ROLE OF THE CEREBELLUM IN DYSTONIA

A 28 year old right handed man presented with a ten year history of difficulty in writing. He had been prescribed metoclopramide for an episode of vomiting one week prior...

Tolerance of early pallidal stimulation in pediatric generalized dystonia

The authors report on 2 cases of pediatric generalized dystonia with a DYT1 mutation; the patients, an 11-year-old girl and a 9-year-old boy, underwent chronic, pallidal deep brain stimulation (DBS) of the globus pallidus internus (GPi). The dystonic postures in both cases showed dramatic improvements with pallidal DBS, but each patient's symptoms gradually recurred within a year, irrespective of exhaustive readjustments of the stimulation settings. After the recurrence of the dystonic symptoms, the DBS leads were replaced within the GPi in one patient (Case 1) and additional DBS leads were implanted into the bilateral subthalamic nuclei in the other patient (Case 2). Neither measure produced any further clinical benefit, and the patient in Case 2 died of status dystonicus 2 days after reoperation. These findings suggest that early pallidal DBS for pediatric dystonia is indeed effective, although there are some cases in which its therapeutic effect is lost. One possible reason may be the ability of the preadolescent brain to tolerate chronic electrical stimuli during the active maturation process.

The environmental epidemiology of primary dystonia.

Dystonia is a movement disorder characterized by involuntary muscle contractions that cause twisting movements and abnormal postures. Primary dystonia is the most common form and is thought to be a multifactorial condition in which one or more genes combine with environmental factors to reach disease. We reviewed controlled studies on possible environmental risk factors for primary early- and late-onset dystonia. Environmental factors associated with primary early-onset dystonia are poorly understood. Early childhood illnesses have been reported to be more frequent in patients with DYT1 dystonia than in subjects carrying the DYT1 mutation that did not manifest dystonia, thus raising the possibility that such exposures precipitate dystonia among DYT1 carriers. Conversely, several environmental factors have been associated with primary adult-onset focal dystonias compared to control subjects. Namely, eye diseases, sore throat, idiopathic scoliosis, and repetitive upper limb motor action seem to be associated with blepharospasm (BSP), laryngeal dystonia (LD), cervical dystonia (CD), and upper limb dystonia, respectively. In addition, an inverse association between coffee drinking and BSP has been observed in both case-unrelated control and family-based case-control studies. Additional evidence supporting a causal link with different forms of primary late-onset dystonia is only available for diseases of the anterior segment of the eye, writing activity, and coffee intake. There is reasonable epidemiological evidence that some environmental factors are risk-modifying factors for specific forms of primary adult-onset focal dystonia.

Sustained relief of generalized dystonia despite prolonged interruption of deep brain stimulation

Pallidal deep brain stimulation (DBS) is an established treatment for disabling, medication-refractory generalized dystonia. Patients typically regress to their preoperative baseline when stimulation is discontinued. Presented are case reports of 2 dystonia patients. Two patients with primary generalized dystonia (1 with the DYT1 mutation) who were treated successfully with bilateral pallidal DBS for periods of 18 months and 5 years retained motor benefit for several months after inadvertent interruption of stimulation. Stimulation was interrupted unilaterally for 3 and 7 months and bilaterally for 2 days and 2 months, respectively. Symptoms of dystonia returned only partially during the period of therapy interruption and rapidly and completely resolved after resuming stimulation. We report unexpected and prolonged retention of motor benefits despite transient cessation of pallidal DBS in 2 dystonia patients. Factors that appear to differentiate these individuals are young age, short duration of disease, and chronic DBS therapy with relatively low energy of stimulation.

TorsinA rescues ER-associated stress and locomotive defects in C. elegans models of ALS

ABSTRACTMolecular mechanisms underlying neurodegenerative diseases converge at the interface of pathways impacting cellular stress, protein homeostasis and aging. Targeting the intrinsic capacities of neuroprotective proteins to restore neuronal function and/or attenuate degeneration represents a potential means toward therapeutic intervention. The product of the human DYT1 gene, torsinA, is a member of the functionally diverse AAA+ family of proteins and exhibits robust molecular-chaperone-like activity, both in vitro and in vivo. Although mutations in DYT1 are associated with a rare form of heritable generalized dystonia, the native function of torsinA seems to be cytoprotective in maintaining the cellular threshold to endoplasmic reticulum (ER) stress. Here we explore the potential for torsinA to serve as a buffer to attenuate the cellular consequences of misfolded-protein stress as it pertains to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The selective vulnerability of motor neurons to degeneration in ALS mouse models harboring mutations in superoxide dismutase (SOD1) has been found to correlate with regional-specific ER stress in brains. Using Caenorhabditis elegans as a system to model ER stress, we generated transgenic nematodes overexpressing either wild-type or mutant human SOD1 to evaluate their relative impact on ER stress induction in vivo. These studies revealed a mutant-SOD1-specific increase in ER stress that was further exacerbated by changes in temperature, all of which was robustly attenuated by co-expression of torsinA. Moreover, through complementary behavioral analysis, torsinA was able to restore normal neuronal function in mutant G85R SOD1 animals. Furthermore, torsinA targeted mutant SOD1 for degradation via the proteasome, representing mechanistic insight on the activity that torsinA has on aggregate-prone proteins. These results expand our understanding of proteostatic mechanisms influencing neuronal dysfunction in ALS, while simultaneously highlighting the potential for torsinA as a novel target for therapeutic development.

Early registration of diffusion tensor images for group tractography of dystonia patients

To make a group comparison of diffusion tensor imaging (DTI) results of dystonia patients and controls to reveal occult pathology. We propose using an early registration method that produces sharper group images and enables us to do group tractography. Twelve dystonia patients manifesting the disease, seven nonmanifesting dystonia mutation carriers (DYT1 and DYT6 gene mutations), and eight age-matched normal control subjects were imaged for a previous study. Early and late registration methods for DTI were compared. An early registration technique for a super set was proposed, in which the diffusion-weighted images were registered to a template, gradient vectors were reoriented for each subject, and they were combined into a super set before tensor calculation. The super set included images from all subjects and was useful for group comparisons. We used results obtained from the early registration of a super set for group analysis of tracts using the deterministic fiber-tracking technique. In dystonia mutation carriers, we detected fewer fibers in the cerebello-thalamo-cortical pathways. This result agrees well with the findings of a previous study that utilized a probabilistic tractography method and demonstrated that gene carriers have less fiber tracts in the disease-involved pathway. This analysis visualized group level white matter fractional anisotropy and tract differences between dystonia patients and controls, and can be useful in understanding the pathophysiology of other nonfocal white matter diseases.

The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin–proteasome pathway and macroautophagy

DYT1 dystonia is a dominantly inherited, disabling neurological disorder with low penetrance that is caused by the deletion of a glutamic acid (ΔE) in the protein torsinA. We previously showed that torsinA(wt) is degraded through macroautophagy while torsinA(ΔE) is targeted to the ubiquitin–proteasome pathway (UPP). The different catabolism of torsinA(wt) and (ΔE) potentially modulates torsinA(wt):torsinA(ΔE) stoichiometry. Therefore, gaining a mechanistic understanding on how the protein quality control machinery clears torsinA(ΔE) in neurons may uncover important regulatory steps in disease pathogenesis. Here, we asked whether F-box/G-domain protein 1 (FBG1), a ubiquitin ligase known to degrade neuronal glycoproteins, is implicated in the degradation of torsinA(ΔE) by the UPP. In a first set of studies completed in cultured cells, we show that FBG1 interacts with and influences the steady-state levels of torsinA(wt) and (ΔE). Interestingly, FBG1 achieves this effect promoting the degradation of torsinA not only through the UPP, but also by macroautophagy. To determine the potential clinical significance of these findings, we asked if eliminating expression of Fbg1 triggers a motor phenotype in torsinA(ΔE) knock in (KI) mice, a model of non-manifesting DYT1 mutation carriers. We detected differences in spontaneous locomotion between aged torsinA(ΔE) KI–Fbg1 knock out and control mice. Furthermore, neuronal levels of torsinA were unaltered in Fbg1 null mice, indicating that redundant systems likely compensate in vivo for the absence of this ubiquitin ligase. In summary, our studies support a non-essential role for FBG1 on the degradation of torsinA and uncover a novel link of FBG1 to the autophagy pathway.