Document Detail

Disruption of dopamine homeostasis underlies selective neurodegeneration mediated by alpha-synuclein.
MedLine Citation:
PMID:  18005066     Owner:  NLM     Status:  MEDLINE    
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.
Soon S Park; Emily M Schulz; Daewoo Lee
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2007-11-14
Journal Detail:
Title:  The European journal of neuroscience     Volume:  26     ISSN:  0953-816X     ISO Abbreviation:  Eur. J. Neurosci.     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-11-21     Completed Date:  2008-02-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8918110     Medline TA:  Eur J Neurosci     Country:  France    
Other Details:
Languages:  eng     Pagination:  3104-12     Citation Subset:  IM    
Neuroscience Program, Department of Biological Sciences, Ohio University, Athens, OH 45701, USA.
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MeSH Terms
Alanine / genetics
Animals, Genetically Modified
Cells, Cultured
Dopamine / metabolism*
Embryo, Nonmammalian
Enzyme Inhibitors / pharmacology
Glutathione / pharmacology
Green Fluorescent Proteins / genetics,  metabolism
Homeostasis / drug effects,  physiology*
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
Reg. No./Substance:
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 3-Monooxygenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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