Primary dystonia: Molecules and mechanisms

Department of Pharmacology, Columbia University, New York, NY, USA.
Nature Reviews Neurology (Impact Factor: 15.36). 10/2009; 5(11):598-609. DOI: 10.1038/nrneurol.2009.160
Source: PubMed


Primary dystonia is characterized by abnormal, involuntary twisting and turning movements that reflect impaired motor system function. The dystonic brain seems normal, in that it contains no overt lesions or evidence of neurodegeneration, but functional brain imaging has uncovered abnormalities involving the cortex, striatum and cerebellum, and diffusion tensor imaging suggests the presence of microstructural defects in white matter tracts of the cerebellothalamocortical circuit. Clinical electrophysiological studies show that the dystonic CNS exhibits aberrant plasticity--perhaps related to deficient inhibitory neurotransmission--in a range of brain structures, as well as the spinal cord. Dystonia is, therefore, best conceptualized as a motor circuit disorder, rather than an abnormality of a particular brain structure. None of the aforementioned abnormalities can be strictly causal, as they are not limited to regions of the CNS subserving clinically affected body parts, and are found in seemingly healthy patients with dystonia-related mutations. The study of dystonia-related genes will, hopefully, help researchers to unravel the chain of events from molecular to cellular to system abnormalities. DYT1 mutations, for example, cause abnormalities within the endoplasmic reticulum-nuclear envelope endomembrane system. Other dystonia-related gene products traffic through the endoplasmic reticulum, suggesting a potential cell biological theme underlying primary dystonia.

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    • "TorsinA is a putative member of the AAA+ superfamily of ATPases associated with different activities (Neuwald et al. 1999). The torsinA mRNA is widely expressed in various human tissues, including the central nervous system, but the biological role of torsinA is not completely clear (reviewed in (Tanabe et al. 2009; Zolkiewski and Wu 2011)). AAA+ ATPases are energy-driven " molecular machines " , which remodel the conformation of macromolecules and disassemble macromolecular complexes (Hanson and Whiteheart 2005). "
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    ABSTRACT: A single GAG codon deletion in the gene encoding torsinA is linked to most cases of early-onset torsion dystonia. TorsinA is an ER-localized membrane-associated ATPase from the AAA+ superfamily with an unknown biological function. We investigated the formation of oligomeric complexes of torsinA in cultured mammalian cells and found that wild type torsinA associates into a complex with a molecular weight consistent with that of a homohexamer. Interestingly, the dystonia-linked variant torsinAΔE displayed a reduced propensity to form the oligomers compared to the wild type protein. We also discovered that the deletion of the N-terminal membrane-associating region of torsinA abolished oligomer formation. Our results demonstrate that the dystonia-linked mutation in the torsinA gene produces a protein variant that is deficient in maintaining its oligomeric state and suggest that ER membrane association is required to stabilize the torsinA complex.
    SpringerPlus 12/2014; 3(1):743. DOI:10.1186/2193-1801-3-743
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    • "As claimed by Tanabe and co-workers, even-though anti-cholinergic medications are effective in DYT1 and other forms of dystonia, this does not necessarily imply a primary role of ACh in these disorders. In point of fact, the abnormal cholinergic functioning may result as a secondary effect of the altered dopaminergic neurotransmission in the striatum (34) and this imbalance may have a role in symptom generation, as showed recently in DYT1 animal models (45). "
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    ABSTRACT: Primary Dystonia (pD) is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Gilles de la Tourette Syndrome (GTS) is a childhood-onset neuropsychiatric developmental disorder characterised by motor and phonic tics, which could progress to behavioural changes. GTS and obsessive-compulsive disorders (OCD) are often seen in comorbidity, also suggesting a possible overlap in the pathophysiological bases of these two conditions. PET techniques are of considerable value in detecting functional and molecular abnormalities in vivo, according to the adopted radioligands. For example, PET is the unique technique that allows in vivo investigation of neurotransmitter systems, providing evidence of changes in GTS or pD. For example, presynaptic and postsynaptic dopaminergic studies with PET have shown alterations compatible with dysfunction or loss of D2-bearing neurons, increased synaptic dopamine levels, or both. Measures of cerebral glucose metabolism with 18F-fluorodeoxyglucose (18F-FDG PET) are very sensitive in showing brain functional alterations as well. 18F-FDG PET data have shown metabolic changes within the cortico-striato-pallido-thalamo-cortical and cerebello-thalamo-cortical networks, revealing possible involvement of brain circuits not limited to basal ganglia in pD and GTS. The aim of this work is to overview PET consistent neuroimaging literature on pD and GTS that has provided functional and molecular knowledge of the underlying neural dysfunction. Furthermore we suggest potential applications of these techniques in monitoring treatments.
    Frontiers in Neurology 07/2014; DOI:10.3389/fneur.2014.00138
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    • "The disease can be of either inherited or sporadic origin in these individuals (Albanese et al. 2011, 2013). The DYT1 and DYT6 genotypes, associated respectively with mutations at the TOR1A and THAP1 loci (Ozelius et al. 1997; Fuchs et al. 2009), represent the most common inherited forms of the disorder (Breakefield et al. 2008; Tanabe et al. 2009). Functional brain imaging studies have revealed stereotyped changes involving motor networks in manifesting and nonmanifesting carriers of these incompletely penetrant dominant traits (Carbon et al. 2008; Carbon and Eidelberg 2009). "
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    ABSTRACT: Dystonia is a brain disorder characterized by abnormal involuntary movements without defining neuropathological changes. The disease is often inherited as an autosomal-dominant trait with incomplete penetrance. Individuals with dystonia, whether inherited or sporadic, exhibit striking phenotypic variability, with marked differences in the somatic distribution and severity of clinical manifestations. In the current study, we used magnetic resonance diffusion tensor imaging to identify microstructural changes associated with specific limb manifestations. Functional MRI was used to localize specific limb regions within the somatosensory cortex. Microstructural integrity was preserved when assessed in subrolandic white matter regions somatotopically related to the clinically involved limbs, but was reduced in regions linked to clinically uninvolved (asymptomatic) body areas. Clinical manifestations were greatest in subjects with relatively intact microstructure in somatotopically relevant white matter regions. Tractography revealed significant phenotype-related differences in the visualized thalamocortical tracts while corticostriatal and corticospinal pathways did not differ between groups. Cerebellothalamic microstructural abnormalities were also seen in the dystonia subjects, but these changes were associated with genotype, rather than with phenotypic variation. The findings suggest that the thalamocortical motor system is a major determinant of dystonia phenotype. This pathway may represent a novel therapeutic target for individuals with refractory limb dystonia.
    Cerebral Cortex 05/2014; 25(9). DOI:10.1093/cercor/bhu104 · 8.67 Impact Factor
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