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Acta Neuropathologica Communications

, 4:108

First Online: 03 October 2016Received: 08 September 2016Accepted: 14 September 2016


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.

KeywordsDystonia DYT1 Dopamine Peripheral injury Second hit Electronic supplementary materialThe online version of this article doi:10.1186-s40478-016-0375-7 contains supplementary material, which is available to authorized users.

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Autor: Chi Wang Ip - Ioannis U. Isaias - Burak B. Kusche-Tekin - Dennis Klein - Janos Groh - Aet O’Leary - Susanne Knorr - Ta


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