| Disruption of dopamine homeostasis underlies selective neurodegeneration mediated by alpha-synuclein. | |
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MedLine Citation:
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PMID: 18005066 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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A key challenge in Parkinson's disease research is to understand mechanisms underlying selective degeneration of dopaminergic neurons mediated by genetic factors such as alpha-synuclein (alpha-Syn). The present study examined whether dopamine (DA)-dependent oxidative stress underlies alpha-Syn-mediated neurodegeneration using Drosophila primary neuronal cultures. Green fluorescent protein (GFP) was used to identify live dopaminergic neurons in primary cultures prepared on a marked photoetched coverslip, which allowed us to repeatedly access preidentified dopaminergic neurons at different time points in a non-invasive manner. This live tracking of GFP-marked dopaminergic neurons revealed age-dependent neurodegeneration mediated by a mutant human alpha-Syn (A30P). Degeneration was rescued when alpha-Syn neuronal cultures were incubated with 1 mm glutathione from Day 3 after culturing. Furthermore, depletion of cytoplasmic DA by 100 microm alpha-methyl-p-tyrosine completely rescued the early stage of alpha-Syn-mediated dopaminergic cell loss, demonstrating that DA plays a major role in oxidative stress-dependent neurodegeneration mediated by alpha-Syn. In contrast, overexpression of a Drosophila tyrosine hydroxylase gene (dTH1) alone caused DA neurodegeneration by enhanced DA synthesis in the cytoplasm. Age-dependent dopaminergic cell loss was comparable in alpha-Syn vs dTH1-overexpressed neuronal cultures, indicating that increased DA levels in the cytoplasm is a critical change downstream of mutant alpha-Syn function. Finally, overexpression of a Drosophila vesicular monoamine transporter rescued alpha-Syn-mediated neurodegeneration through enhanced sequestration of cytoplasmic DA into synaptic vesicles, further indicating that a main cause of selective neurodegeneration is alpha-Syn-induced disruption of DA homeostasis. All of these results demonstrate that elevated cytoplasmic DA is a main factor underlying the early stage of alpha-Syn-mediated neurodegeneration. |
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Authors:
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Soon S Park; Emily M Schulz; Daewoo Lee |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2007-11-14 |
Journal Detail:
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Title: The European journal of neuroscience Volume: 26 ISSN: 0953-816X ISO Abbreviation: Eur. J. Neurosci. Publication Date: 2007 Dec |
Date Detail:
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Created Date: 2007-11-21 Completed Date: 2008-02-25 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8918110 Medline TA: Eur J Neurosci Country: France |
Other Details:
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Languages: eng Pagination: 3104-12 Citation Subset: IM |
Affiliation:
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Neuroscience Program, Department of Biological Sciences, Ohio University, Athens, OH 45701, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alanine
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genetics Animals Animals, Genetically Modified Cells, Cultured Dopamine / metabolism* Drosophila Embryo, Nonmammalian Enzyme Inhibitors / pharmacology Glutathione / pharmacology Green Fluorescent Proteins / genetics, metabolism Homeostasis / drug effects, physiology* Humans Indoles / diagnostic use Mutation / physiology Nerve Degeneration / chemically induced, drug therapy, metabolism* Proline / genetics Receptors, Dopamine D1 / genetics, metabolism* Time Factors Tyrosine 3-Monooxygenase / metabolism Vesicular Monoamine Transport Proteins / metabolism alpha-Methyltyrosine / pharmacology alpha-Synuclein / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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NS050260/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Indoles; 0/Receptors, Dopamine D1; 0/Vesicular Monoamine Transport Proteins; 0/alpha-Synuclein; 147-85-3/Proline; 147336-22-9/Green Fluorescent Proteins; 47165-04-8/DAPI; 56-41-7/Alanine; 658-48-0/alpha-Methyltyrosine; 70-18-8/Glutathione; EC 1.14.16.2/Tyrosine 3-Monooxygenase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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