Source:http://linkedlifedata.com/resource/pubmed/id/17785456
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
43
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| pubmed:dateCreated |
2007-10-22
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| pubmed:abstractText |
The mechanisms that govern the formation of alpha-synuclein (alpha-syn) aggregates are not well understood but are considered a central event in the pathogenesis of Parkinson's disease (PD). A critically important modulator of alpha-syn aggregation in vitro is dopamine and other catechols, which can prevent the formation of alpha-syn aggregates in cell-free and cellular model systems. Despite the profound importance of this interaction for the pathogenesis of PD, the processes by which catechols alter alpha-syn aggregation are unclear. Molecular and biochemical approaches were employed to evaluate the mechanism of catechol-alpha-syn interactions and the effect on inclusion formation. The data show that the intracellular inhibition of alpha-syn aggregation requires the oxidation of catechols and the specific noncovalent interaction of the oxidized catechols with residues (125)YEMPS(129) in the C-terminal region of the protein. Cell-free studies using novel near infrared fluorescence methodology for the detection of covalent protein-ortho-quinone adducts showed that although covalent modification of alpha-syn occurs, this does not affect alpha-syn fibril formation. In addition, oxidized catechols are unable to prevent both thermal and acid-induced protein aggregation as well as fibrils formed from a protein that lacks a YEMPS amino acid sequence, suggesting a specific effect for alpha-syn. These results suggest that inappropriate C-terminal cleavage of alpha-syn, which is known to occur in vivo in PD brain or a decline of intracellular catechol levels might affect disease progression, resulting in accelerated alpha-syn inclusion formation and dopaminergic neurodegeneration.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Catechols,
http://linkedlifedata.com/resource/pubmed/chemical/Formazans,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-Synuclein,
http://linkedlifedata.com/resource/pubmed/chemical/nitroblue formazan
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| pubmed:status |
MEDLINE
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| pubmed:month |
Oct
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| pubmed:issn |
0021-9258
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
26
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| pubmed:volume |
282
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
31621-30
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| pubmed:meshHeading |
pubmed-meshheading:17785456-Amino Acid Sequence,
pubmed-meshheading:17785456-Catechols,
pubmed-meshheading:17785456-Cell Line, Tumor,
pubmed-meshheading:17785456-Cell-Free System,
pubmed-meshheading:17785456-Fluorescent Antibody Technique, Indirect,
pubmed-meshheading:17785456-Formazans,
pubmed-meshheading:17785456-Genetic Vectors,
pubmed-meshheading:17785456-Humans,
pubmed-meshheading:17785456-Lentivirus,
pubmed-meshheading:17785456-Light,
pubmed-meshheading:17785456-Mass Spectrometry,
pubmed-meshheading:17785456-Neuroblastoma,
pubmed-meshheading:17785456-Oxidation-Reduction,
pubmed-meshheading:17785456-Plasmids,
pubmed-meshheading:17785456-Recombinant Proteins,
pubmed-meshheading:17785456-Scattering, Radiation,
pubmed-meshheading:17785456-Spectrometry, Fluorescence,
pubmed-meshheading:17785456-Transduction, Genetic,
pubmed-meshheading:17785456-Transfection,
pubmed-meshheading:17785456-alpha-Synuclein
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| pubmed:year |
2007
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| pubmed:articleTitle |
Cellular oligomerization of alpha-synuclein is determined by the interaction of oxidized catechols with a C-terminal sequence.
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| pubmed:affiliation |
Joseph Stokes Jr. Research Institute, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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