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Critical Reviews in Biochemistry and... 2015Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity... (Review)
Review
Torsin ATPases (Torsins) belong to the widespread AAA+ (ATPases associated with a variety of cellular activities) family of ATPases, which share structural similarity but have diverse cellular functions. Torsins are outliers in this family because they lack many characteristics of typical AAA+ proteins, and they are the only members of the AAA+ family located in the endoplasmic reticulum and contiguous perinuclear space. While it is clear that Torsins have essential roles in many, if not all metazoans, their precise cellular functions remain elusive. Studying Torsins has significant medical relevance since mutations in Torsins or Torsin-associated proteins result in a variety of congenital human disorders, the most frequent of which is early-onset torsion (DYT1) dystonia, a severe movement disorder. A better understanding of the Torsin system is needed to define the molecular etiology of these diseases, potentially enabling corrective therapy. Here, we provide a comprehensive overview of the Torsin system in metazoans, discuss functional clues obtained from various model systems and organisms and provide a phylogenetic and structural analysis of Torsins and their regulatory cofactors in relation to disease-causative mutations. Moreover, we review recent data that have led to a dramatically improved understanding of these machines at a molecular level, providing a foundation for investigating the molecular defects underlying the associated movement disorders. Lastly, we discuss our ideas on how recent progress may be utilized to inform future studies aimed at determining the cellular role(s) of these atypical molecular machines and their implications for dystonia treatment options.
Topics: Amino Acid Sequence; Animals; Carrier Proteins; Disease Models, Animal; Dystonia Musculorum Deformans; HSC70 Heat-Shock Proteins; Humans; Membrane Proteins; Molecular Chaperones; Molecular Sequence Data; Mutation; Protein Transport; Sequence Alignment
PubMed: 26592310
DOI: 10.3109/10409238.2015.1091804 -
Nature Cell Biology Nov 2022DYT1 dystonia is a debilitating neurological movement disorder arising from mutation in the AAA+ ATPase TorsinA. The hallmark of Torsin dysfunction is nuclear envelope...
DYT1 dystonia is a debilitating neurological movement disorder arising from mutation in the AAA+ ATPase TorsinA. The hallmark of Torsin dysfunction is nuclear envelope blebbing resulting from defects in nuclear pore complex biogenesis. Whether blebs actively contribute to disease manifestation is unknown. We report that FG-nucleoporins in the bleb lumen form aberrant condensates and contribute to DYT1 dystonia by provoking two proteotoxic insults. Short-lived ubiquitylated proteins that are normally rapidly degraded partition into the bleb lumen and become stabilized. In addition, blebs selectively sequester a specific HSP40-HSP70 chaperone network that is modulated by the bleb component MLF2. MLF2 suppresses the ectopic accumulation of FG-nucleoporins and modulates the selective properties and size of condensates in vitro. Our study identifies dual mechanisms of proteotoxicity in the context of condensate formation and establishes FG-nucleoporin-directed activities for a nuclear chaperone network.
Topics: Humans; Dystonia; Nuclear Envelope; Nuclear Pore Complex Proteins
PubMed: 36302970
DOI: 10.1038/s41556-022-01001-y -
Neurobiology of Disease Jan 2021X-linked Dystonia Parkinsonism (XDP) is a recessive, genetically inherited neurodegenerative disorder endemic to Panay Island in the Philippines. Clinical symptoms... (Review)
Review
X-linked Dystonia Parkinsonism (XDP) is a recessive, genetically inherited neurodegenerative disorder endemic to Panay Island in the Philippines. Clinical symptoms include the initial appearance of dystonia, followed by parkinsonian traits after 10-15 years. The basal ganglia, particularly the striatum, is an area of focus in XDP neuropathology research, as the striatum shows marked atrophy that correlates with disease progression. Thus, XDP shares features of Parkinson's disease symptomatology, in addition to the genetic predisposition and presence of striatal atrophy resembling Huntington's disease. However, further research is required to reveal the detailed pathology and indicators of disease in the XDP brain. First, there are limited neuropathological studies that have investigated neuronal changes and neuroinflammation in the XDP brain. However, multiple neuroimaging studies on XDP patients provide clues to other affected brain regions. Furthermore, molecular pathological studies have elucidated that the main genetic cause of XDP is in the TAF-1 gene, but how this mutation relates to XDP neuropathology still remains to be fully investigated. Hence, we aim to provide an extensive overview of the current literature describing neuropathological changes within the XDP brain, and discuss future research avenues, which will provide a better understanding of XDP neuropathogenesis.
Topics: Basal Ganglia; Brain; Diffusion Magnetic Resonance Imaging; Dystonic Disorders; Genetic Diseases, X-Linked; Humans; Magnetic Resonance Imaging; Neostriatum
PubMed: 33227492
DOI: 10.1016/j.nbd.2020.105186 -
Science Translational Medicine May 2023Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be a neural circuit disorder with dysfunction arising within...
Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be a neural circuit disorder with dysfunction arising within and between multiple brain regions. Given that spinal neural circuits constitute the final pathway for motor control, we sought to determine their contribution to this movement disorder. Focusing on the most common inherited form of dystonia in humans, DYT1-, we generated a conditional knockout of the torsin family 1 member A () gene in the mouse spinal cord and dorsal root ganglia (DRG). We found that these mice recapitulated the phenotype of the human condition, developing early-onset generalized torsional dystonia. Motor signs emerged early in the mouse hindlimbs before spreading caudo-rostrally to affect the pelvis, trunk, and forelimbs throughout postnatal maturation. Physiologically, these mice bore the hallmark features of dystonia, including spontaneous contractions at rest and excessive and disorganized contractions, including cocontractions of antagonist muscle groups, during voluntary movements. Spontaneous activity, disorganized motor output, and impaired monosynaptic reflexes, all signs of human dystonia, were recorded from isolated mouse spinal cords from these conditional knockout mice. All components of the monosynaptic reflex arc were affected, including motor neurons. Given that confining the conditional knockout to DRG did not lead to early-onset dystonia, we conclude that the pathophysiological substrate of this mouse model of dystonia lies in spinal neural circuits. Together, these data provide new insights into our current understanding of dystonia pathophysiology.
Topics: Humans; Mice; Animals; Dystonia; Dystonia Musculorum Deformans; Mice, Knockout; Brain; Molecular Chaperones
PubMed: 37134150
DOI: 10.1126/scitranslmed.adg3904 -
Neurology Apr 2021To report 4 novel mutations leading to laryngeal and cervical dystonia with frequent generalization.
OBJECTIVE
To report 4 novel mutations leading to laryngeal and cervical dystonia with frequent generalization.
METHODS
We screened 4 families including a total of 11 definitely affected members with a clinical picture resembling the original description.
RESULTS
Four novel variants in the gene have been identified: D295N, R46M, Q424H, and R121W. In silico modeling showed that all variants have characteristics similar to R2G. The variants segregate with the disease in 3 of the families with evidence of incomplete penetrance in 2 of them. All 4 variants would be classified as likely pathogenic. The clinical picture particularly included laryngeal dystonia (often the site of onset), associated with cervical and upper limb dystonia and frequent generalization. Laryngeal dystonia was extremely prevalent (>90%) both in the original cases and in this case series. The hobby horse gait was evident in only 1 patient in this case series.
CONCLUSIONS
Our interpretation is that laryngeal involvement is a hallmark feature of DYT-TUBB4A. Nevertheless, mutations remain an exceedingly rare cause of laryngeal or other isolated dystonia.
Topics: Adolescent; Adult; Child; Child, Preschool; Dystonia; Dystonia Musculorum Deformans; Female; Humans; Male; Middle Aged; Pedigree; Polymorphism, Single Nucleotide; Tubulin; Voice Disorders; Young Adult
PubMed: 32943487
DOI: 10.1212/WNL.0000000000010882 -
Brain and Behavior Jun 2023Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically... (Review)
Review
BACKGROUND
Primary generalized dystonia due to the DYT1 gene is an autosomal dominant disorder caused by a GAG deletion on chromosome 9q34. It is a well-defined, genetically proven, isolated dystonia syndrome. However, its pathophysiology remains unclear.
OBJECTIVES
This study was aimed at profiling the functional neuroimaging findings in DYT1 dystonia and harmonizing the pathophysiological implications for DYT1 dystonia from the standpoint of different neuroimaging techniques.
METHODS
A systematic review was conducted using identified studies published in English from Medline, PsycINFO, Embase, CINAHL, and the Cochrane Database of Systematic Reviews (CDSR), between 1985 and December 2019 (PROSPERO protocol CRD42018111211).
RESULTS
All DYT1 gene carriers irrespective of clinical penetrance have reduced striatal GABA, dopamine receptors and increased metabolic activity in the lentiform nucleus, supplementary motor area, and cerebellum in addition to an abnormal cerebellothalamocortical pathway. Nonmanifesting carriers on the other hand have a disruption of the distal (thalamocortical) segment and have larger putaminal volumes than manifesting carriers and healthy controls. Activation of the midbrain, thalamus, and sensorimotor cortex was only found in the manifesting carriers.
CONCLUSIONS
Therefore, we propose that DYT1 dystonia is a cerebellostriatothalamocortical network disorder affecting either the structure or function of the different structures or nodes in the network.
Topics: Humans; Dystonia; Dystonic Disorders; Molecular Chaperones; Neuroimaging
PubMed: 37165749
DOI: 10.1002/brb3.3023 -
Movement Disorders : Official Journal... Nov 2017Dystonia is a common movement disorder that devastates the lives of many patients, but the etiology of this disorder remains poorly understood. Dystonia has... (Review)
Review
Dystonia is a common movement disorder that devastates the lives of many patients, but the etiology of this disorder remains poorly understood. Dystonia has traditionally been considered a disorder of the basal ganglia. However, growing evidence suggests that the cerebellum may be involved in certain types of dystonia, raising several questions. Can different types of dystonia be classified as either a basal ganglia disorder or a cerebellar disorder? Is dystonia a network disorder that involves the cerebellum and basal ganglia? If dystonia is a network disorder, how can we target treatments to alleviate symptoms in patients? A recent study by Chen et al, using the pharmacological mouse model of rapid-onset dystonia parkinsonism, has provided some insight into these important questions. They showed that the cerebellum can directly modulate basal ganglia activity through a short latency cerebello-thalamo-basal ganglia pathway. Further, this article and others have provided evidence that in some cases, aberrant cerebello-basal ganglia communication can be involved in dystonia. In this review we examine the evidence for the involvement of the cerebellum and cerebello-basal ganglia interactions in dystonia. We conclude that there is ample evidence to suggest that the cerebellum plays a role in some dystonias, including the early-onset primary torsion dystonia DYT1 and that further studies examining the role of this brain region and its interaction with the basal ganglia in dystonia are warranted. © 2017 International Parkinson and Movement Disorder Society.
Topics: Animals; Basal Ganglia; Cerebellum; Dystonic Disorders; Humans
PubMed: 28843013
DOI: 10.1002/mds.27123 -
Journal of Neurochemistry Jun 2009A GAG deletion in the DYT1 gene is responsible for the autosomal dominant movement disorder, early onset primary torsion dystonia, which is characterised by involuntary... (Review)
Review
A GAG deletion in the DYT1 gene is responsible for the autosomal dominant movement disorder, early onset primary torsion dystonia, which is characterised by involuntary sustained muscle contractions and abnormal posturing of the limbs. The mutation leads to deletion of a single glutamate residue in the C-terminus of the protein torsinA, a member of the AAA+ ATPase family of proteins with multiple functions. Since no evidence of neurodegeneration has been found in DYT1 patients, the dystonic phenotype is likely to be the result of neuronal functional defect(s), the nature of which is only partially understood. Biochemical, structural and cell biological studies have been performed in order to characterise torsinA. These studies, together with the generation of several animal models, have contributed to identify cellular compartments and pathways, including the cytoskeleton and the nuclear envelope, the secretory pathway and the synaptic vesicle machinery where torsinA function may be crucial. However, the role of torsinA and the correlation between the dysfunction caused by the mutation and the dystonic phenotype remain unclear. This review provides an overview of the findings of the last ten years of research on torsinA, a critical evaluation of the different models proposed and insights towards future avenues of research.
Topics: Animals; Central Nervous System; Disease Models, Animal; Dystonia; Humans; Molecular Chaperones; Synapses
PubMed: 19457118
DOI: 10.1111/j.1471-4159.2009.06095.x -
Orphanet Journal of Rare Diseases Nov 2006Early onset torsion dystonia (EOTD) is a rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more... (Review)
Review
Early onset torsion dystonia (EOTD) is a rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more sites of the body. A US study estimated the prevalence at approximately 1 in 30,000. The estimated prevalence in the general population of Europe seems to be lower, ranging from 1 in 330,000 to 1 in 200,000, although precise numbers are currently not available. The estimated prevalence in the Ashkenazi Jewish population is approximately five to ten times higher, due to a founder mutation. Symptoms of EOTD typically develop first in an arm or leg in middle to late childhood and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years. Distribution and severity of symptoms vary widely between affected individuals. The majority of cases from various ethnic groups are caused by an autosomal dominantly inherited deletion of 3 bp (GAG) in the DYT1 gene on chromosome 9q34. This gene encodes a protein named torsinA, which is presumed to act as a chaperone protein associated with the endoplasmic reticulum and the nuclear envelope. It may interact with the dopamine transporter and participate in intracellular trafficking, although its precise function within the cell remains to be determined. Molecular genetic diagnostic and genetic counseling is recommended for individuals with age of onset below 26 years, and may also be considered in those with onset after 26 years having a relative with typical early onset dystonia. Treatment options include botulinum toxin injections for focal symptoms, pharmacological therapy such as anticholinergics (most commonly trihexiphenydil) for generalized dystonia and surgical approaches such as deep brain stimulation of the internal globus pallidus or intrathecal baclofen application in severe cases. All patients have normal cognitive function, and despite a high rate of generalization of dystonia, 75% of those patients are able to maintain ambulation and independence, and therefore a comparatively good quality of life, with modern treatment modalities.
Topics: Age of Onset; Dystonia Musculorum Deformans; Europe; Genetic Testing; Humans; Molecular Chaperones; Prevalence; United States
PubMed: 17129379
DOI: 10.1186/1750-1172-1-48 -
Postgraduate Medical Journal Feb 1978A patient was admitted to hospital following an overdose of phenobarbital. During her recovery she developed both chorea and torsion dystonia which could only be related...
A patient was admitted to hospital following an overdose of phenobarbital. During her recovery she developed both chorea and torsion dystonia which could only be related to her high plasma phenobarbital levels.
Topics: Adult; Chorea; Dyskinesia, Drug-Induced; Humans; Male; Phenobarbital; Poisoning
PubMed: 634871
DOI: 10.1136/pgmj.54.628.114