Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 34, Pages 12551-12556Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806065105
Keywords
basal ganglia; movement disorders; Parkinson's disease; striatum
Categories
Funding
- Japan Ministry of Education, Science, Culture and Sports [1610J-1]
- National Institutes of Health (MGH/MIT Parkinson's Disease Research Center) [PS50 NS38372]
- National Parkinson Foundation
- [1500240]
- [16590255]
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Dopa-responsive dystonia (DRD) is a hereditary dystonia characterized by a childhood onset of fixed dystonic posture with a dramatic and sustained response to relatively low doses of levodopa. DRD is thought to result from striatal dopamine deficiency due to a reduced synthesis and activity of tyrosine hydroxylase (TH), the synthetic enzyme for dopamine. The mechanisms underlying the genesis of dystonia in DRD present a challenge to models of basal ganglia movement control, given that striatal dopamine deficiency is the hallmark of Parkinson's disease. We report here behavioral and anatomical observations on a transgenic mouse model for DRD in which the gene for 6-pyruvoyl-tetrahydropterin synthase is targeted to render selective dysfunction of TH synthesis in the striatum. Mutant mice exhibited motor deficits phenotypically resembling symptoms of human DRD and manifested a major depletion of TH labeling in the striatum, with a marked posterior-to-anterior gradient resulting in near total loss caudally. Strikingly, within the regions of remaining TH staining in the striatum, there was a greater loss of TH labeling in striosomes than in the surrounding matrix. The predominant loss of TH expression in striosomes occurred during the early postnatal period, when motor symptoms first appeared. We suggest that the differential striosome-matrix pattern of dopamine loss could be a key to identifying the mechanisms underlying the genesis of dystonia in DRD.
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