Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 19, Pages 8043-8048Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0900358106
Keywords
astrocytes; Parkinson's disease; extraneuronal monoamine transporter; dopamine; methamphetamine
Categories
Funding
- National Institutes of Health [ES014899, P30 ES01247, T32 ES07026, NS0641912, NS062180, NS042269, NS3837009, AG021617]
- National Institute of Environmental Health Sciences [ES014899-02S1]
- U. S. Department of Defense [W81WXWH-08-1-0465, W81WXWH-08-1-0522]
- Parkinson's Disease Foundation
- Thomas Hartman Foundation for Parkinson's Research
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Toxic organic cations can damage nigrostriatal dopaminergic pathways as seen in most parkinsonian syndromes and in some cases of illicit drug exposure. Here, we show that the organic cation transporter 3 (Oct3) is expressed in nondopaminergic cells adjacent to both the soma and terminals of midbrain dopaminergic neurons. We hypothesized that Oct3 contributes to the dopaminergic damage by bidirectionally regulating the local bioavailability of toxic species. Consistent with this view, Oct3 deletion and pharmacological inhibition hampers the release of the toxic organic cation 1-methyl-4-phenylpyridinium from astrocytes and protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration in mice. Furthermore, Oct3 deletion impairs the removal of the excess extracellular dopamine induced by methamphetamine and enhances striatal dopaminergic terminal damage caused by this psychostimulant. These results may have far-reaching implications for our understanding of the mechanism of cell death in a wide range of neurodegenerative diseases and may open new avenues for neuroprotective intervention.
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