Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury

Chi Wang Ip, Ioannis U. Isaias, Burak B. Kusche-Tekin, Dennis Klein, Janos Groh, Aet O'Leary, Susanne Knorr, Takahiro Higuchi, James B. Koprich, Jonathan M. Brotchie, Klaus V. Toyka, Andreas Reif, Jens Volkmann

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Article number108
JournalActa Neuropathologica Communications
Volume4
Issue number1
DOIs
Publication statusPublished - Jan 1 2016
Externally publishedYes

Fingerprint

Corpus Striatum
Peripheral Nerve Injuries
Dystonia
Dopamine Plasma Membrane Transport Proteins
Nerve Crush
Dopamine
Dyskinesias
Hindlimb
Hindlimb Suspension
Dystonic Disorders
Dopamine D1 Receptors
Dopamine D2 Receptors
Penetrance
Levodopa
Mesencephalon
Autoradiography
Posture
Gait
Peripheral Nerves
Dissection

Keywords

  • Dopamine
  • Dystonia
  • DYT1
  • Peripheral injury
  • Second hit

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury. / Ip, Chi Wang; Isaias, Ioannis U.; Kusche-Tekin, Burak B.; Klein, Dennis; Groh, Janos; O'Leary, Aet; Knorr, Susanne; Higuchi, Takahiro; Koprich, James B.; Brotchie, Jonathan M.; Toyka, Klaus V.; Reif, Andreas; Volkmann, Jens.

In: Acta Neuropathologica Communications, Vol. 4, No. 1, 108, 01.01.2016.

Research output: Contribution to journalArticle

Ip, CW, Isaias, IU, Kusche-Tekin, BB, Klein, D, Groh, J, O'Leary, A, Knorr, S, Higuchi, T, Koprich, JB, Brotchie, JM, Toyka, KV, Reif, A & Volkmann, J 2016, 'Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury', Acta Neuropathologica Communications, vol. 4, no. 1, 108. https://doi.org/10.1186/s40478-016-0375-7
Ip, Chi Wang ; Isaias, Ioannis U. ; Kusche-Tekin, Burak B. ; Klein, Dennis ; Groh, Janos ; O'Leary, Aet ; Knorr, Susanne ; Higuchi, Takahiro ; Koprich, James B. ; Brotchie, Jonathan M. ; Toyka, Klaus V. ; Reif, Andreas ; Volkmann, Jens. / Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury. In: Acta Neuropathologica Communications. 2016 ; Vol. 4, No. 1.
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