Expanded polyglutamine stretches lead to aberrant transcriptional regulation in polyglutamine diseases.
At least nine neurodegenerative diseases are known to be caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches have been suggested, the molecular mechanisms of neurodegeneration remain unclear. We demonstrated that the nuclear translocation of mutant proteins containing expanded polyQ stretches is a prerequisite for the expression of their cytotoxicity. Hypothesizing that nuclear proteins that interact with mutant proteins, particularly, those that bind to the expanded polyQ stretches, are involved in the pathogenetic mechanisms underlying neurodegeneration, we screened nuclear proteins for their capability of binding to expanded polyQ stretches. We found that expanded polyQ stretches preferentially bind to TAF[symbol: see text]130, a coactivator involved in CREB-dependent transcriptional activation. The binding of TAF[symbol: see text]130 with expanded polyQ stretches strongly suppress CREB-dependent transcriptional activation, suggesting that interference with transcription due to the binding of expanded polyQ stretches with TAF[symbol: see text]130 and redistribution of TAF[symbol: see text]130 are involved in the pathogenetic mechanisms underlying neurodegeneration.
Shimohata
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Department of Neurology, Brain Research Institute, Niigata University. tsuji@cc.niigata-u.ac.jp
Onodera
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Tsuji
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D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D019680:Trinucleotide Repeat Expansion
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010455:Peptides; C101882:TAF4 protein, human; D035381:TATA-Binding Protein Associated Factors; D035362:Transcription Factor TFIID; D014157:Transcription Factors; C097188:polyglutamine