Spasticity and spastic dystonia: the two faces of velocity-dependent hypertonia

BackgroundSpasticity and spastic dystonia are two separate phenomena of the upper motor neuron syndrome. Spasticity is clinically defined by velocity-dependent hypertonia and tendon jerk hyperreflexia due to the hyper-excitability of the stretch reflex. Spastic dystonia is the inability to relax a muscle leading to a spontaneous tonic contraction. Both spasticity and spastic dystonia are present in patients who are at rest; however, only patients with spasticity are actually able to kept their muscles relaxed prior to muscle stretch. The idea that has inspired the present work is that also in patients with spastic dystonia the stretch reflex is likely to be hyper-excitable. Therefore, velocity-dependent hypertonia could be mediated not only by spasticity, but also by spastic dystonia.MethodsTonic stretch reflexes in the rectus femoris muscle were evoked in 30 patients with multiple sclerosis showing velocity-dependent hypertonia of leg extensors and the habituation of the reflex was studied. Moreover, the capability of relax the muscle prior to muscle stretch (spastic dystonia) was also investigated.ResultsA tonic stretch reflex was evoked in all the enrolled patients. 73% of the patients were able to relax their rectus femoris muscle prior to stretch (spasticity). In the overwhelming majority of these patients, the tonic stretch reflex decreased during repeated stretches. In the remaining 27% of the subjects, the muscle was tonically activated prior to muscle stretch (spastic dystonia). In the patients in whom spastic dystonia progressively increased over the subsequent stretches (50% of the subjects with spastic dystonia), the habituation of the reflex was replaced by a progressive reflex facilitation.DiscussionThis study shows for the first time that velocity-dependent hypertonia can be caused by two distinct phenomena: spasticity and spastic dystonia. The habituation of the tonic stretch reflex, which is a typical feature of spasticity, is replaced by a reflex facilitation in the half of the subject with spastic dystonia. These preliminary findings suggest that differentiating the two types of velocity-dependent muscle hypertonia (spasticity and spastic dystonia) could be clinically relevant.     

Hereditäre Dystonien

Dystonias are a clinically and causally heterogeneous group of movement disorders characterized by involuntary muscle contractions that lead to twisting, turning and repetitive movements that can be very painful. Isolated (primary) dystonia is classified clinically as a disease in which dystonia is the only neurological symptom (with or without tremor). Dystonia accompanied by other clinical symptoms (such as parkinsonism or myoclonus) is classified as combined dystonia (dystonia-plus). However, dystonia can be a symptom of any disease of the central nervous system that affects the motor system (e.g. neurodegenerative, ischemic, traumatic processes). During the last 20 years, the development of new molecular genetic technologies has led to the discovery of new genes underlying many dystonia subtypes and to a deeper understanding of the pathophysiology of dystonia. Furthermore, new classification schemes have emerged. This review provides an overview of the genetically determined dystonias, with emphasis on the so-called isolated and combined forms. The summary of phenotypic characteristics associated with specific genetic mutations should enable the clinician to initiate appropriate molecular genetic diagnostics on the basis of concrete clinical manifestations.     

Modeling movement disorders--CRPS-related dystonia explained by abnormal proprioceptive reflexes

Humans control their movements using adaptive proprioceptive feedback from muscle afferents. The interaction between proprioceptive reflexes and biomechanical properties of the limb is essential in understanding the etiology of movement disorders. A non-linear neuromuscular model of the wrist incorporating muscle dynamics and neural control was developed to test hypotheses on fixed dystonia. Dystonia entails sustained muscle contractions resulting in abnormal postures. Lack of inhibition is often hypothesized to result in hyperreflexia (exaggerated reflexes), which may cause fixed dystonia. In this study the model-simulated behavior in case of several abnormal reflex settings was compared to the clinical features of dystonia: abnormal posture, sustained muscle contraction, increased stiffness, diminished voluntary control and activity-aggravation. The simulation results were rated to criteria based on characteristic features of dystonia. Three abnormal reflex scenarios were tested: (1) increased reflex sensitivity-increased sensitivity of both the agonistic and antagonistic reflex pathways; (2) imbalanced reflex offset-a static offset to the reflex pathways on the agonistic side only; and (3) imbalanced reflex sensitivity-increased sensitivity of only the agonistic reflex pathways. Increased reflex sensitivity did not fully account for the features of dystonia, despite distinct motor dysfunction, since no abnormal postures occurred. Although imbalanced reflex offset did result in an abnormal posture, it could not satisfy other criteria. Nevertheless, imbalanced reflex sensitivity with unstable force feedback in one of the antagonists closely resembled all features of dystonia. The developed neuromuscular model is an effective tool to test hypotheses on the underlying pathophysiology of movement disorders.     

Abnormal motor patterns in the framework of the equilibrium-point hypothesis: a cause for dystonic movements?

Until now, the equilibrium-point hypothesis (λ model) of motor control has assumed nonintersecting force-length characteristics of the tonic stretch reflex for individual muscles. Limited data from animal experiments suggest, however, that such intersections may occur. We have assumed the possibility of intersection of the characteristics of the tonic stretch reflex and performed a computer simulation of movement trajectories and electromyographic patterns. The simulation has demonstrated, in particular, that a transient change in the slope of the characteristic of an agonist muscle may lead to temporary movement reversals, hesitations, oscillations, and multiple electromyographic bursts that are typical of movements of patients with dystonia. The movement patterns of three patients with idiopathic dystonia during attempts at fast single-joint movements (in the elbow, wrist, and ankle) were recorded and compared with the results of the computer simulation. This approach considers that motor disorders in dystonia result from faulty control patterns that may not correlate with any morphological or neurophysiological changes. It provides a basis for the high variability of dystonic movements. The uniqueness of abnormal motor patterns in dystonia, that precludes statistical analysis across patients, may result from subtle differences in the patterns of intersecting characteristics of the tonic stretch reflex. The applicability of our analysis to disordered multijoint movement patterns is discussed. Received: 26 July 1993/Accepted in revised form: 22 December 1993     

Mutational and biochemical analysis of dopamine in dystonia

The dystonias are a group of serious movement disorders characterized by involuntary muscle spasms of different parts of the body. We recently proposed that hypofunction of dopamine D₂ receptor-mediated inhibition of the indirect output pathway of the basal ganglia can result in dystonia. In this review, we discuss the results of a variety of genetic and biochemical studies in light of this hypothesis. Several forms of early-onset dystonia show distinct autosomal dominant, recessive, or X-linked genetic transmission patterns. Late onset forms of dystonia, though not showing clear Mendelian transmission patterns, also appear to be highly familial. Recently, several genetic-linkage locations have been identified for early-onset dystonia and for two of these loci, mutations decreasing dopamine synthesis have been demonstrated. Biochemical studies of monkeys and man also demonstrate that several types of dystonia occur in a dopamine-deficiency state. Similarly, mice strains developed to be deficient in several dopamine-pathway components have motor abnormalities consistent with dystonia. Hypofunction of the dopamine D₂ receptormediated inhibition of the indirect output pathway of the putamen may be a common feature of many of these heritable and secondary dystonic syndromes.     

Abnormal Movement Preparation in Task-Specific Focal Hand Dystonia

Electrophysiological and behavioral studies in primary dystonia suggest abnormalities during movement preparation, but this crucial phase preceding movement onset has not yet been studied specifically with functional magnetic resonance imaging (fMRI). To identify abnormalities in brain activation during movement preparation, we used event-related fMRI to analyze behaviorally unimpaired sequential finger movements in 18 patients with task-specific focal hand dystonia (FHD) and 18 healthy subjects. Patients and controls executed self-initiated or externally cued prelearnt four-digit sequential movements using either right or left hands. In FHD patients, motor performance of the sequential finger task was not associated with task-related dystonic posturing and their activation levels during motor execution were highly comparable with controls. On the other hand reduced activation was observed during movement preparation in the FHD patients in left premotor cortex / precentral gyrus for all conditions, and for self-initiation additionally in supplementary motor area, left mid-insula and anterior putamen, independent of effector side. Findings argue for abnormalities of early stages of motor control in FHD, manifesting during movement preparation. Since deficits map to regions involved in the coding of motor programs, we propose that task-specific dystonia is characterized by abnormalities during recruitment of motor programs: these do not manifest at the behavioral level during simple automated movements, however, errors in motor programs of complex movements established by extensive practice (a core feature of FHD), trigger the inappropriate movement patterns observed in task-specific dystonia.     

Comparative analysis of background activity of ventrolateral thalamic neurons in patients with parkinsonism and torsion muscle dystonia

In the course of neurosurgical interventions in 40 patients with parkinsonism and torsion muscle dystonia, the background activity (BA) was recorded from 124 neurons of the ventrolateral nucleus (VL) of the thalamus with the aid of microelectrodes during demarcation of boundaries between nuclear structures, and identification of zones within a nucleus. The following characteristic features of the BA in patients with parkinsonism were found: a relatively large proportion (71%) of cells with a burst pattern of activity; a great diversity of burst duration in the activity (short or prolonged bursts); a large proportion (67%) of cells with cyclic changes in the BA frequency; diverse patterns of cyclic modulation, where periods varied from fractions of a second (0.2–0.8 sec) to seconds (2–10 sec) or to tens of seconds (20–40 sec); cyclic successions of spike bursts with the rhythm typical of the peripheral tremor (3–7/sec) in a substantial proportion (40%) of the units.The background spike trains recorded in patients with torsion muscle dystonia consisted of separated spikes in the majority (69%) of units. Only short high-frequency discharges were found in the burst activity in this group; a cyclic BA pattern occurred much less frequently (in 23% of neurons); burst discharges at a 3–4/sec frequency were found only in 4% of the examined cells.The possible nature of motor disorders in patients with parkinsonism and torsion muscle dystonia and the mechanisms of the curing effects of cryodestruction of theVL of the thalamus in the treatment of the disease are discussed.Neirofiziologiya/Neurophysiology, Vol. 25, No. 4, pp. 246–253, July–August, 1993.     

Fixed Dystonia in Complex Regional Pain Syndrome: a Descriptive and Computational Modeling Approach

Background  

Complex regional pain syndrome (CRPS) may occur after trauma, usually to one limb, and is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. Involvement of dysfunctional GABAergic interneurons has been suggested, however the mechanisms that underpin fixed dystonia are still unknown. We hypothesized that dystonia could be the result of aberrant proprioceptive reflex strengths of position, velocity or force feedback.     

Minimal Change in the Cytoplasmic Calcium Dynamics in Striatal GABAergic Neurons of a DYT1 Dystonia Knock-In Mouse Model

DYT1 dystonia is the most common hereditary form of primary torsion dystonia. This autosomal-dominant disorder is characterized by involuntary muscle contractions that cause sustained twisting and repetitive movements. It is caused by an in-frame deletion in the TOR1A gene, leading to the deletion of a glutamic acid residue in the torsinA protein. Heterozygous knock-in mice, which reproduce the genetic mutation in human patients, have abnormalities in synaptic transmission at the principal GABAergic neurons in the striatum, a brain structure that is involved in the execution and modulation of motor activity. However, whether this mutation affects the excitability of striatal GABAergic neurons has not been investigated in this animal model. Here, we examined the excitability of cultured striatal neurons obtained from heterozygous knock-in mice, using calcium imaging as indirect readout. Immunofluorescence revealed that more than 97% of these neurons are positive for a marker of GABAergic neurons, and that more than 92% are also positive for a marker of medium spiny neurons, indicating that these are mixed cultures of mostly medium spiny neurons and a few (~5%) GABAergic interneurons. When these neurons were depolarized by field stimulation, the calcium concentration in the dendrites increased rapidly and then decayed slowly. The amplitudes of calcium transients were larger in heterozygous neurons than in wild-type neurons, resulting in ~15% increase in cumulative calcium transients during a train of stimuli. However, there was no change in other parameters of calcium dynamics. Given that calcium dynamics reflect neuronal excitability, these results suggest that the mutation only slightly increases the excitability of striatal GABAergic neurons in DYT1 dystonia.     

The pathophysiological basis of dystonias

Dystonias comprise a group of movement disorders that are characterized by involuntary movements and postures. Insight into the nature of neuronal dysfunction has been provided by the identification of genes responsible for primary dystonias, the characterization of animal models and functional evaluations and in vivo brain imaging of patients with dystonia. The data suggest that alterations in neuronal development and communication within the brain create a susceptible substratum for dystonia. Although there is no overt neurodegeneration in most forms of dystonia, there are functional and microstructural brain alterations. Dystonia offers a window into the mechanisms whereby subtle changes in neuronal function, particularly in sensorimotor circuits that are associated with motor learning and memory, can corrupt normal coordination and lead to a disabling motor disorder.     

Integration of Sensory Force Feedback Is Disturbed in CRPS-Related Dystonia

Complex regional pain syndrome (CRPS) is characterized by pain and disturbed blood flow, temperature regulation and motor control. Approximately 25% of cases develop fixed dystonia. The origin of this movement disorder is poorly understood, although recent insights suggest involvement of disturbed force feedback. Assessment of sensorimotor integration may provide insight into the pathophysiology of fixed dystonia. Sensory weighting is the process of integrating and weighting sensory feedback channels in the central nervous system to improve the state estimate. It was hypothesized that patients with CRPS-related dystonia bias sensory weighting of force and position toward position due to the unreliability of force feedback. The current study provides experimental evidence for dysfunctional sensory integration in fixed dystonia, showing that CRPS-patients with fixed dystonia weight force and position feedback differently than controls do. The study shows reduced force feedback weights in CRPS-patients with fixed dystonia, making it the first to demonstrate disturbed integration of force feedback in fixed dystonia, an important step towards understanding the pathophysiology of fixed dystonia.     

Lipid and fatty acid variations in muscle tissues of the ‘yellow’ stage of the European eel (Anguilla anguilla) during short-term adaptation to freshwater and seawater under food deprivation

Changes in body mass and water content (WC), lipids, and fatty acid (FA) composition of muscle were determined in European eels (Anguilla anguilla) in the ‘yellow’ stage (sexually immature). The animals were held in either freshwater (FW) or seawater (SW) and deprived of food for four weeks. During this period, body mass decreased steadily. This decrease was accompanied by reduced muscle WC and total lipid in both SW and FW. ‘Yellow’ eels appeared to use lipids in muscle to provide metabolic and osmoregulatory energy. However, they maintained relative constancy in the FA profiles, so that total FA, saturated, monounsaturated, and polyunsaturated FA, were similar between salinities during short-term starvation.     

4-Phenylbutyrate Attenuates the ER Stress Response and Cyclic AMP Accumulation in DYT1 Dystonia Cell Models

Dystonia is a neurological disorder in which sustained muscle contractions induce twisting and repetitive movements or abnormal posturing. DYT1 early-onset primary dystonia is the most common form of hereditary dystonia and is caused by deletion of a glutamic acid residue (302/303) near the carboxyl-terminus of encoded torsinA. TorsinA is localized primarily within the contiguous lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), and is hypothesized to function as a molecular chaperone and an important regulator of the ER stress-signaling pathway, but how the mutation in torsinA causes disease remains unclear. Multiple lines of evidence suggest that the clinical symptoms of dystonia result from abnormalities in dopamine (DA) signaling, and possibly involving its down-stream effector adenylate cyclase that produces the second messenger cyclic adenosine-3′, 5′-monophosphate (cAMP). Here we find that mutation in torsinA induces ER stress, and inhibits the cyclic adenosine-3′, 5′-monophosphate (cAMP) response to the adenylate cyclase agonist forskolin. Both defective mechanins are corrected by the small molecule 4-phenylbutyrate (4-PBA) that alleviates ER stress. Our results link torsinA, the ER-stress-response, and cAMP-dependent signaling, and suggest 4-PBA could also be used in dystonia treatment. Other pharmacological agents known to modulate the cAMP cascade, and ER stress may also be therapeutic in dystonia patients and can be tested in the models described here, thus supplementing current efforts centered on the dopamine pathway.     

Abnormalities in Amino Acid Neurotransmitters in Discrete Brain Regions of Genetically Dystonic Hamsters

The concentrations of 11 amino acids, including the neurotransmitters gamma-aminobutyric acid, glutamate, aspartate, glycine, and taurine, were determined by HPLC in 12 brain regions of genetically dystonic (dtSZ) hamsters and age-matched nondystonic controls. Since dystonia in mutant dtSZ hamsters is transient and disappears after about 70 days of age, amino acids were determined at the age of maximum severity of dystonia (30-40 days) and after disappearance of the disease, to examine which neurochemical changes were related to dystonia. In dtSZ hamsters with the maximum severity of dystonia, significant changes in concentrations of the neurotransmitters gamma-aminobutyric acid, glutamate, aspartate, and taurine were found in several regions involved in motor functions, e.g., cerebellum, thalamus, and corpus striatum. Most of these changes were not permanent but disappeared in parallel with dystonia, implicating a causal relationship between altered aminoacidergic neurotransmission and dystonia in mutant dtSZ hamsters.     

Effect of experimental muscle pain on maximal voluntary activation of human biceps brachii muscle

Muscle pain has widespread effects on motor performance, but the effect of pain on voluntary activation, which is the level of neural drive to contracting muscle, is not known. To determine whether induced muscle pain reduces voluntary activation during maximal voluntary contractions, voluntary activation of elbow flexors was assessed with both motor-point stimulation and transcranial magnetic stimulation over the motor cortex. In addition, we performed a psychophysical experiment to investigate the effect of induced muscle pain across a wide range of submaximal efforts (5-75% maximum). In all studies, elbow flexion torque was recorded before, during, and after experimental muscle pain by injection of 1 ml of 5% hypertonic saline into biceps. Injection of hypertonic saline evoked deep pain in the muscle (pain rating ～5 on a scale from 0 to 10). Experimental muscle pain caused a small (～5%) but significant reduction of maximal voluntary torque in the motor-point and motor cortical studies (P < 0.001 and P = 0.045, respectively; n = 7). By contrast, experimental muscle pain had no significant effect on voluntary activation when assessed with motor-point and motor cortical stimulation although voluntary activation tested with motor-point stimulation was reduced by ～2% in contractions after pain had resolved (P = 0.003). Furthermore, induced muscle pain had no significant effect on torque output during submaximal efforts (P > 0.05; n = 6), which suggests that muscle pain did not alter the relationship between the sense of effort and production of voluntary torque. Hence, the present study suggests that transient experimental muscle pain in biceps brachii has a limited effect on central motor pathways.     

Waist Circumference,BMI, and Visceral Adipose Tissue in White Women and Women of African Descent

Although waist circumference (WC) is a marker of visceral adipose tissue (VAT), WC cut‐points are based on BMI category. We compared WC‐BMI and WC‐VAT relationships in blacks and whites. Combining data from five studies, BMI and WC were measured in 1,409 premenopausal women (148 white South Africans, 607 African‐Americans, 186 black South Africans, 445 West Africans, 23 black Africans living in United States). In three of five studies, participants had VAT measured by computerized tomography (n = 456). Compared to whites, blacks had higher BMI (29.6 ± 7.6 (mean ± s.d.) vs. 27.6 ± 6.6 kg/m², P = 0.001), similar WC (92 ± 16 vs. 90 ± 15 cm, P = 0.27) and lower VAT (64 ± 42 vs. 101 ± 59 cm², P < 0.001). The WC‐BMI relationship did not differ by race (blacks: β (s.e.) WC = 0.42 (.01), whites: β (s.e.) WC = 0.40 (0.01), P = 0.73). The WC‐VAT relationship was different in blacks and whites (blacks: β (s.e.) WC = 1.38 (0.11), whites: β (s.e.) WC = 3.18 (0.21), P < 0.001). Whites had a greater increase in VAT per unit increase in WC. WC‐BMI and WC‐VAT relationships did not differ among black populations. As WC‐BMI relationship did not differ by race, the same BMI‐based WC guidelines may be appropriate for black and white women. However, if WC is defined by VAT, race‐specific WC thresholds are required.     

Transplantation of Xenopus laevis Tissues to Determine the Ability of Motor Neurons to Acquire a Novel Target

The evolutionary origin of novelties is a central problem in biology. At a cellular level this requires, for example, molecularly resolving how brainstem motor neurons change their innervation target from muscle fibers (branchial motor neurons) to neural crest-derived ganglia (visceral motor neurons) or ear-derived hair cells (inner ear and lateral line efferent neurons). Transplantation of various tissues into the path of motor neuron axons could determine the ability of any motor neuron to innervate a novel target. Several tissues that receive direct, indirect, or no motor innervation were transplanted into the path of different motor neuron populations in Xenopus laevis embryos. Ears, somites, hearts, and lungs were transplanted to the orbit, replacing the eye. Jaw and eye muscle were transplanted to the trunk, replacing a somite. Applications of lipophilic dyes and immunohistochemistry to reveal motor neuron axon terminals were used. The ear, but not somite-derived muscle, heart, or liver, received motor neuron axons via the oculomotor or trochlear nerves. Somite-derived muscle tissue was innervated, likely by the hypoglossal nerve, when replacing the ear. In contrast to our previous report on ear innervation by spinal motor neurons, none of the tissues (eye or jaw muscle) was innervated when transplanted to the trunk. Taken together, these results suggest that there is some plasticity inherent to motor innervation, but not every motor neuron can become an efferent to any target that normally receives motor input. The only tissue among our samples that can be innervated by all motor neurons tested is the ear. We suggest some possible, testable molecular suggestions for this apparent uniqueness.     

The effect of fast and slow motor unit activation on whole-muscle mechanical performance: the size principle may not pose a mechanical paradox

The output of skeletal muscle can be varied by selectively recruiting different motor units. However, our knowledge of muscle function is largely derived from muscle in which all motor units are activated. This discrepancy may limit our understanding of in vivo muscle function. Hence, this study aimed to characterize the mechanical properties of muscle with different motor unit activation. We determined the isometric properties and isotonic force–velocity relationship of rat plantaris muscles in situ with all of the muscle active, 30% of the muscle containing predominately slower motor units active or 20% of the muscle containing predominately faster motor units active. There was a significant effect of active motor unit type on isometric force rise time (p < 0.001) and the force–velocity relationship (p < 0.001). Surprisingly, force rise time was longer and maximum shortening velocity higher when all motor units were active than when either fast or slow motor units were selectively activated. We propose this is due to the greater relative effects of factors such as series compliance and muscle resistance to shortening during sub-maximal contractions. The findings presented here suggest that recruitment according to the size principle, where slow motor units are activated first and faster ones recruited as demand increases, may not pose a mechanical paradox, as has been previously suggested.     

Recessive Mutations in the α3 (VI) Collagen Gene COL6A3 Cause Early-Onset Isolated Dystonia

Isolated dystonia is a disorder characterized by involuntary twisting postures arising from sustained muscle contractions. Although autosomal-dominant mutations in TOR1A, THAP1, and GNAL have been found in some cases, the molecular mechanisms underlying isolated dystonia are largely unknown. In addition, although emphasis has been placed on dominant isolated dystonia, the disorder is also transmitted as a recessive trait, for which no mutations have been defined. Using whole-exome sequencing in a recessive isolated dystonia-affected kindred, we identified disease-segregating compound heterozygous mutations in COL6A3, a collagen VI gene associated previously with muscular dystrophy. Genetic screening of a further 367 isolated dystonia subjects revealed two additional recessive pedigrees harboring compound heterozygous mutations in COL6A3. Strikingly, all affected individuals had at least one pathogenic allele in exon 41, including an exon-skipping mutation that induced an in-frame deletion. We tested the hypothesis that disruption of this exon is pathognomonic for isolated dystonia by inducing a series of in-frame deletions in zebrafish embryos. Consistent with our human genetics data, suppression of the exon 41 ortholog caused deficits in axonal outgrowth, whereas suppression of other exons phenocopied collagen deposition mutants. All recessive mutation carriers demonstrated early-onset segmental isolated dystonia without muscular disease. Finally, we show that Col6a3 is expressed in neurons, with relevant mRNA levels detectable throughout the adult mouse brain. Taken together, our data indicate that loss-of-function mutations affecting a specific region of COL6A3 cause recessive isolated dystonia with underlying neurodevelopmental deficits and highlight the brain extracellular matrix as a contributor to dystonia pathogenesis.     

TorsinA protein degradation and autophagy in DYT1 dystonia

Early-onset generalized dystonia (DYT1) is a debilitating neurological disorder characterized by involuntary movements and sustained muscle spasms. DYT1 dystonia has been associated with two mutations in torsinA that result in the deletion of a single glutamate residue (torsinA DeltaE) and six amino-acid residues (torsinA Delta323-8). We recently revealed that torsinA, a peripheral membrane protein, which resides predominantly in the lumen of the endoplasmic reticulum (ER) and nuclear envelope (NE), is a long-lived protein whose turnover is mediated by basal autophagy. Dystonia-associated torsinA DeltaE and torsinA Delta323-8 mutant proteins show enhanced retention in the NE and accelerated degradation by both the proteasome and autophagy. Our results raise the possibility that the monomeric form of torsinA mutant proteins is cleared by proteasome-mediated ER-associated degradation (ERAD), whereas the oligomeric and aggregated forms of torsinA mutant proteins are cleared by ER stress-induced autophagy. Our findings provide new insights into the pathogenic mechanism of torsinA DeltaE and torsinA Delta323-8 mutations in dystonia and emphasize the need for a mechanistic understanding of the role of autophagy in protein quality control in the ER and NE compartments.