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Author Notes:

Address correspondence to: Louis Ptácek or Ying-Hui Fu, Department of Neurology, UCSF MC 2922, 548F Rock Hall, 1550 Fourth St., San Francisco, California 94158-2324, USA. Phone: 415.502.5614; Fax: 415.502.5641; E-mail: ljp@ucsf.edu (L. Ptácek); ying-hui.fu@ucsf.edu (Y.-H. Fu).

We thank Anatol Kreitzer and Shu-Ting Lin for helpful discussions.

Conflict of interest: The authors have declared that no conflict of interest exists.

L.J. Ptácek is an investigator of the Howard Hughes Medical Institute.

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Research Funding:

This work was supported by grants from the Dystonia Medical Research Foundation, the Bachmann-Strauss Dystonia & Parkinson Foundation, NIH grant U54 RR19481, the Sandler Neurogenetics Fund, and P30 NS047243 (Tufts Center for Neuroscience Research).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • MEDICINE, RESEARCH & EXPERIMENTAL
  • NON-KINESIGENIC DYSKINESIA
  • BASAL GANGLIA
  • RECEPTOR INTERACTIONS
  • PARKINSONS-DISEASE
  • MYOFIBRILLOGENESIS REGULATOR-1
  • DYSTONIC CHOREOATHETOSIS
  • CHROMOSOME 2Q
  • RAT MODEL
  • GENE
  • ADENOSINE

Dopamine dysregulation in a mouse model of paroxysmal nonkinesigenic dyskinesia

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Journal Title:

Journal of Clinical Investigation

Volume:

Volume 122, Number 2

Publisher:

, Pages 507-518

Type of Work:

Article | Final Publisher PDF

Abstract:

Paroxysmal nonkinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder. Patients have episodes that last 1 to 4 hours and are precipitated by alcohol, coffee, and stress. Previous research has shown that mutations in an uncharacterized gene on chromosome 2q33-q35 (which is termed PNKD) are responsible for PNKD. Here, we report the generation of antibodies specific for the PNKD protein and show that it is widely expressed in the mouse brain, exclusively in neurons. One PNKD isoform is a membrane-associated protein. Transgenic mice carrying mutations in the mouse Pnkd locus equivalent to those found in patients with PNKD recapitulated the human PNKD phenotype. Staining for cfos demonstrated that administration of alcohol or caffeine induced neuronal activity in the basal ganglia in these mice. They also showed nigrostriatal neurotransmission deficits that were manifested by reduced extracellular dopamine levels in the striatum and a proportional increase of dopamine release in response to caffeine and ethanol treatment. These findings support the hypothesis that the PNKD protein functions to modulate striatal neurotransmitter release in response to stress and other precipitating factors. Copyright © 2012, American Society for Clinical Investigation.

Copyright information:

© 2012, American Society for Clinical Investigation

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