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rdf:type |
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lifeskim:mentions |
umls-concept:C0012634,
umls-concept:C0024408,
umls-concept:C0208355,
umls-concept:C0301625,
umls-concept:C0332120,
umls-concept:C0332621,
umls-concept:C0384782,
umls-concept:C0475264,
umls-concept:C1314939,
umls-concept:C1366904,
umls-concept:C1533691
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pubmed:issue |
4
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pubmed:dateCreated |
1999-4-29
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pubmed:abstractText |
Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), is one of at least eight inherited neurodegenerative diseases caused by expansion of a polyglutamine tract in the disease protein. Here we present two lines of evidence implicating the ubiquitin-proteasome pathway in SCA3/MJD pathogenesis. First, studies of both human disease tissue and in vitro models showed redistribution of the 26S proteasome complex into polyglutamine aggregates. In neurons from SCA3/MJD brain, the proteasome localized to intranuclear inclusions containing the mutant protein, ataxin-3. In transfected cells, the proteasome redistributed into inclusions formed by three expanded polyglutamine proteins: a pathologic ataxin-3 fragment, full-length mutant ataxin-3 and an unrelated GFP-polyglutamine fusion protein. Inclusion formation by the full-length mutant ataxin-3 required nuclear localization of the protein and occurred within specific subnuclear structures recently implicated in the regulation of cell death, promyelocytic leukemia antigen oncogenic domains. In a second set of experiments, inhibitors of the proteasome caused a repeat length-dependent increase in aggregate formation, implying that the proteasome plays a direct role in suppressing polyglutamine aggregation in disease. These results support a central role for protein misfolding in the pathogenesis of SCA3/MJD and suggest that modulating proteasome activity is a potential approach to altering the progression of this and other polyglutamine diseases.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/ATXN3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Acetylcysteine,
http://linkedlifedata.com/resource/pubmed/chemical/Atxn3 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Endopeptidases,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Proteinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Multienzyme Complexes,
http://linkedlifedata.com/resource/pubmed/chemical/Nerve Tissue Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Nuclear Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Proteasome Endopeptidase Complex,
http://linkedlifedata.com/resource/pubmed/chemical/Repressor Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/lactacystin,
http://linkedlifedata.com/resource/pubmed/chemical/polyglutamine
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0964-6906
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
8
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
673-82
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:10072437-Acetylcysteine,
pubmed-meshheading:10072437-Adult,
pubmed-meshheading:10072437-Animals,
pubmed-meshheading:10072437-Brain,
pubmed-meshheading:10072437-Brain Chemistry,
pubmed-meshheading:10072437-COS Cells,
pubmed-meshheading:10072437-Cell Line,
pubmed-meshheading:10072437-Cell Nucleus,
pubmed-meshheading:10072437-Cysteine Endopeptidases,
pubmed-meshheading:10072437-Cysteine Proteinase Inhibitors,
pubmed-meshheading:10072437-Dose-Response Relationship, Drug,
pubmed-meshheading:10072437-HeLa Cells,
pubmed-meshheading:10072437-Humans,
pubmed-meshheading:10072437-Immunohistochemistry,
pubmed-meshheading:10072437-Inclusion Bodies,
pubmed-meshheading:10072437-Leukemia, Promyelocytic, Acute,
pubmed-meshheading:10072437-Machado-Joseph Disease,
pubmed-meshheading:10072437-Male,
pubmed-meshheading:10072437-Multienzyme Complexes,
pubmed-meshheading:10072437-Mutation,
pubmed-meshheading:10072437-Nerve Tissue Proteins,
pubmed-meshheading:10072437-Nuclear Proteins,
pubmed-meshheading:10072437-Oncogene Proteins,
pubmed-meshheading:10072437-PC12 Cells,
pubmed-meshheading:10072437-Peptides,
pubmed-meshheading:10072437-Proteasome Endopeptidase Complex,
pubmed-meshheading:10072437-Protein Structure, Tertiary,
pubmed-meshheading:10072437-Rats,
pubmed-meshheading:10072437-Rats, Sprague-Dawley,
pubmed-meshheading:10072437-Repressor Proteins
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pubmed:year |
1999
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pubmed:articleTitle |
Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro.
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pubmed:affiliation |
Department of Neurology, University of Iowa College of Medicine, Iowa City, IA 52242, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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