Abstract
Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0375-7) contains supplementary material, which is available to authorized users.
Highlights
Dystonia is a clinical syndrome characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both
Tor1a+/- mice develop more severe dystonia-like movements than wt mice after sciatic nerve crush Two days after nerve injury, tail suspension tests revealed severe weakness of sciatic nerve innervated muscles leading to extension of the right hind leg (Fig. 1a)
Repetitive, involuntary muscle contractions with clenching of the toes and retraction of the affected leg were detected in both wt and Tor1a+/- mice resembling focal dystonia-like movements (Fig. 1b) with a peak at four weeks after surgery followed by a continuous slow decrease of the DLMS in both genotypes
Summary
Dystonia is a clinical syndrome characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonia has multiple acquired and genetic factors most likely converging to a multistep pathophysiological pathway leading to a central motor network disorder with a dystonic phenotype [26, 37]. DYT1 is the most common form of inherited dystonia and is linked to a GAG deletion on the torsinA encoding gene Tor1a. The penetrance of the typical human limb onset generalized DYT1 dystonia phenotype is present in only 30-40 % of gene carriers [28]. Because dystonia can be caused by a trauma [24, 51, 57] or by repetitive limb overuse, and in the absence of a known genetic
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