title: Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury.
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.
authors.affiliation: Department of Neurology, University Hospital of Würzburg, University of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany. ip_c@ukw.de.
authors.forename: Chi Wang
authors.identifier: 0000-0003-0484-385X
authors.initials: CW
authors.lastname: Ip
authors.affiliation: Department of Neurology, University Hospital of Würzburg, University of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
authors.forename: Ioannis U
authors.initials: IU
authors.lastname: Isaias
authors.affiliation: Department of Neurology, University Hospital of Würzburg, University of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
authors.forename: Burak B
authors.initials: BB
authors.lastname: Kusche-Tekin
authors.affiliation: Department of Neurology, University Hospital of Würzburg, University of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Klein
authors.affiliation: Department of Neurology, University Hospital of Würzburg, University of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
authors.forename: Janos
authors.initials: J
authors.lastname: Groh
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Aet
authors.initials: A
authors.lastname: O'Leary
authors.affiliation: Department of Neurology, University Hospital of Würzburg, University of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Knorr
authors.affiliation: Department of Nuclear Medicine, University Hospital of Würzburg, University of Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Higuchi
authors.affiliation: Toronto Western Hospital, University Health Network, 100 King St W, Suite 5600, Toronto, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Koprich
authors.affiliation: Toronto Western Hospital, University Health Network, 100 King St W, Suite 5600, Toronto, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
authors.affiliation: Department of Neurology, University Hospital of Würzburg, University of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Goethe-University Frankfurt, Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reif
authors.affiliation: Department of Neurology, University Hospital of Würzburg, University of Würzburg, Josef-Schneider-Strasse 11, 97080, Würzburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Volkmann
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004421:Dystonia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005684:Gait / Q000187:drug effects / Q000502:physiology; D006614:Hindlimb / Q000503:physiopathology; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007980:Levodopa / Q000494:pharmacology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology
chemical_list: C000600618:DRD2 protein, mouse; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; C583261:Drd1 protein, mouse; C491548:Dyt1 protein, mouse; D018832:Molecular Chaperones; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D007980:Levodopa; D004298:Dopamine
keywords: DYT1; Dopamine; Dystonia; Peripheral injury; Second hit