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rdf:type |
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lifeskim:mentions |
umls-concept:C0007634,
umls-concept:C0011065,
umls-concept:C0024660,
umls-concept:C0026336,
umls-concept:C0043393,
umls-concept:C0220806,
umls-concept:C0243041,
umls-concept:C0270952,
umls-concept:C0332621,
umls-concept:C0392756,
umls-concept:C0521009,
umls-concept:C1522492
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pubmed:issue |
14
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pubmed:dateCreated |
2002-4-1
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pubmed:abstractText |
Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is characterized pathologically by intranuclear inclusions in skeletal muscles and is caused by the expansion of a 10-alanine stretch to 12-17 alanines in the intranuclear poly(A)-binding protein 2 (PABP2). Whereas PABP2 is a major component of the inclusions in OPMD, the pathogenic mechanisms causing disease are unknown. Here we show that polyalanine expansions in PABP2 cause increased numbers of inclusions and enhance death in COS-7 cells. We observed similar increases of protein aggregation and cell death with nuclear-targeted green fluorescent protein linked to longer versus shorter polyalanine stretches. Intranuclear aggregates in our OPMD cell model were associated with heat shock protein (HSP) 40 (HDJ-1) and HSP70. Human HDJ-1, yeast hsp104, a bacterially derived GroEL minichaperone, and the chemical chaperone Me(2)SO reduced both aggregation and cell death in our OPMD model without affecting the levels of PABP2, and similar trends were seen with green fluorescent protein with long polyalanine stretches. Thus, polyalanine expansion mutations in different protein contexts cause proteins to misfold/aggregate and kill cells. The situation in OPMD appears to have many parallels with polyglutamine diseases, raising the possibility that misfolded, aggregate-prone proteins may perturb similar pathways, irrespective of the nature of the mutation or protein context.
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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/Alanine,
http://linkedlifedata.com/resource/pubmed/chemical/Chaperonin 60,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Green Fluorescent Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/HSP40 Heat-Shock Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Heat-Shock Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/HsP104 protein, S cerevisiae,
http://linkedlifedata.com/resource/pubmed/chemical/Luminescent Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Molecular Chaperones,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Poly(A)-Binding Protein II,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Saccharomyces cerevisiae Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/polyalanine
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
5
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pubmed:volume |
277
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
12263-9
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:11796717-Alanine,
pubmed-meshheading:11796717-Animals,
pubmed-meshheading:11796717-Blotting, Western,
pubmed-meshheading:11796717-COS Cells,
pubmed-meshheading:11796717-Chaperonin 60,
pubmed-meshheading:11796717-DNA-Binding Proteins,
pubmed-meshheading:11796717-Green Fluorescent Proteins,
pubmed-meshheading:11796717-HSP40 Heat-Shock Proteins,
pubmed-meshheading:11796717-Heat-Shock Proteins,
pubmed-meshheading:11796717-Humans,
pubmed-meshheading:11796717-Immunohistochemistry,
pubmed-meshheading:11796717-Luminescent Proteins,
pubmed-meshheading:11796717-Molecular Chaperones,
pubmed-meshheading:11796717-Muscular Dystrophies,
pubmed-meshheading:11796717-Peptides,
pubmed-meshheading:11796717-Plasmids,
pubmed-meshheading:11796717-Poly(A)-Binding Protein II,
pubmed-meshheading:11796717-Protein Binding,
pubmed-meshheading:11796717-Protein Folding,
pubmed-meshheading:11796717-Recombinant Fusion Proteins,
pubmed-meshheading:11796717-Saccharomyces cerevisiae Proteins,
pubmed-meshheading:11796717-Time Factors,
pubmed-meshheading:11796717-Transfection
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pubmed:year |
2002
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pubmed:articleTitle |
Mammalian, yeast, bacterial, and chemical chaperones reduce aggregate formation and death in a cell model of oculopharyngeal muscular dystrophy.
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pubmed:affiliation |
Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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