Source:http://linkedlifedata.com/resource/pubmed/id/15591046
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
9
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| pubmed:dateCreated |
2005-2-28
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| pubmed:abstractText |
The accumulation of aggregated alpha-synuclein is thought to contribute to the pathogenesis of Parkinson's disease. Recent studies indicate that aggregated alpha-synuclein binds to S6', a component of the 19 S subunit in the 26 S proteasome and inhibits 26 S proteasomal degradation, both ubiquitin-independent and ubiquitin-dependent. The IC(50) of aggregated alpha-synuclein for inhibition of the 26 S ubiquitin-independent proteasomal activity is approximately 1 nm. alpha-Synuclein has two close homologues, termed beta-synuclein and gamma-synuclein. In the present study we compared the effects of the three synuclein homologues on proteasomal activity. The proteasome exists as a 26 S and a 20 S species, with the 26 S proteasome containing the 20 S core and 19 S cap. Monomeric alpha- and beta-synucleins inhibited the 20 S and 26 S proteasomal activities only weakly, but monomeric gamma-synuclein strongly inhibited ubiquitin-independent proteolysis. The IC(50) of monomeric gamma-synuclein for the 20 S proteolysis was 400 nm. In monomeric form, none of the three synuclein proteins inhibited 26 S ubiquitin-dependent proteasomal activity. Although beta-synuclein had no direct effect on proteasomal activity, co-incubating monomeric beta-synuclein with aggregated alpha-synuclein antagonized the inhibition of the 26 S ubiquitin-independent proteasome by aggregated alpha-synuclein when added before the aggregated alpha-synuclein. Co-incubating beta-synuclein with gamma-synuclein had no effect on the inhibition of the 20 S proteasome by monomeric gamma-synuclein. Immunoprecipitation and pull-down experiments suggested that antagonism by beta-synuclein resulted from binding to alpha-synuclein rather than binding to S6'. Pull-down experiments demonstrated that recombinant monomeric beta-synuclein does not interact with the proteasomal subunit S6', unlike alpha-synuclein, but beta-synuclein does bind alpha-synuclein and competes with S6' for binding to alpha-synuclein. Based on these data, we hypothesize that the alpha- and gamma-synucleins regulate proteasomal function and that beta-synuclein acts as a negative regulator of alpha-synuclein.
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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/ATP dependent 26S protease,
http://linkedlifedata.com/resource/pubmed/chemical/Chymotrypsin,
http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/SNCA protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/SNCB protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Synucleins,
http://linkedlifedata.com/resource/pubmed/chemical/Ubiquitin,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-Synuclein,
http://linkedlifedata.com/resource/pubmed/chemical/beta-Synuclein,
http://linkedlifedata.com/resource/pubmed/chemical/gamma-Synuclein
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| pubmed:status |
MEDLINE
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| pubmed:month |
Mar
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| pubmed:issn |
0021-9258
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| pubmed:author |
pubmed-author:FestoffBarryB,
pubmed-author:HashimotoMakotoM,
pubmed-author:HsuCindyC,
pubmed-author:MasliahEliazerE,
pubmed-author:MatouschekAndreasA,
pubmed-author:MensahKwameK,
pubmed-author:SnyderHeatherH,
pubmed-author:SurguchevaIrina GIG,
pubmed-author:SurguchovAndreiA,
pubmed-author:WolozinBenjaminB
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| pubmed:issnType |
Print
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| pubmed:day |
4
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| pubmed:volume |
280
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
7562-9
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| pubmed:dateRevised |
2007-11-14
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| pubmed:meshHeading |
pubmed-meshheading:15591046-Brain,
pubmed-meshheading:15591046-Cell Line,
pubmed-meshheading:15591046-Chymotrypsin,
pubmed-meshheading:15591046-Dose-Response Relationship, Drug,
pubmed-meshheading:15591046-Humans,
pubmed-meshheading:15591046-Immunoblotting,
pubmed-meshheading:15591046-Inhibitory Concentration 50,
pubmed-meshheading:15591046-Models, Biological,
pubmed-meshheading:15591046-Nerve Tissue Proteins,
pubmed-meshheading:15591046-Proteasome Endopeptidase Complex,
pubmed-meshheading:15591046-Protein Binding,
pubmed-meshheading:15591046-Protein Structure, Tertiary,
pubmed-meshheading:15591046-Recombinant Proteins,
pubmed-meshheading:15591046-Synucleins,
pubmed-meshheading:15591046-Time Factors,
pubmed-meshheading:15591046-Transfection,
pubmed-meshheading:15591046-Ubiquitin,
pubmed-meshheading:15591046-alpha-Synuclein,
pubmed-meshheading:15591046-beta-Synuclein,
pubmed-meshheading:15591046-gamma-Synuclein
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| pubmed:year |
2005
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| pubmed:articleTitle |
beta-Synuclein reduces proteasomal inhibition by alpha-synuclein but not gamma-synuclein.
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| pubmed:affiliation |
Department of Pharmacology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.
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