Abstract
PQBP-1 was isolated on the basis of its interaction with polyglutamine tracts. In this study, using in vitro and in vivo assays, we show that the association between ataxin-1 and PQBP-1 is positively influenced by expanded polyglutamine sequences. In cell lines, interaction between the two molecules induces apoptotic cell death. As a possible mechanism underlying this phenomenon, we found that mutant ataxin-1 enhances binding of PQBP-1 to the C-terminal domain of RNA polymerase II large subunit (Pol II). This reduces the level of phosphorylated Pol II and transcription. Our results suggest the involvement of PQBP-1 in the pathology of spinocerebellar ataxia type 1 (SCA1) and support the idea that modified transcription underlies polyglutamine-mediated pathology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Animals
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Ataxin-1
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Ataxins
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Carrier Proteins / genetics*
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Carrier Proteins / metabolism
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Cell Death / genetics*
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Cell Nucleus / pathology
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Cell Survival / genetics
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Cells, Cultured
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Cerebellum / metabolism*
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Cerebellum / pathology
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Cerebellum / physiopathology
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DNA-Binding Proteins
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Disease Models, Animal
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Female
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Genes, Regulator / genetics*
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Humans
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Inclusion Bodies / genetics
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Inclusion Bodies / metabolism
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Inclusion Bodies / pathology
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Macromolecular Substances
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Mice
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Neurons / metabolism*
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Neurons / pathology
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Peptides / genetics
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Protein Structure, Tertiary / genetics
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RNA Polymerase II / genetics
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RNA Polymerase II / metabolism
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Spinocerebellar Ataxias / genetics*
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Spinocerebellar Ataxias / metabolism
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Spinocerebellar Ataxias / pathology
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Trinucleotide Repeat Expansion / genetics
Substances
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ATXN1 protein, human
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Ataxin-1
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Ataxins
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Atxn1 protein, mouse
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Carrier Proteins
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DNA-Binding Proteins
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Macromolecular Substances
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Nerve Tissue Proteins
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Nuclear Proteins
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PQBP1 protein, human
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Peptides
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Pqbp1 protein, mouse
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polyglutamine
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RNA Polymerase II