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Interaction of expanded polyglutamine stretches with nuclear transcription factors leads to aberrant transcriptional regulation in polyglutamine diseases
Author(s) -
Shimohata Takayoshi,
Onodera Osamu,
Tsuji Shoji
Publication year - 2000
Publication title -
neuropathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.701
H-Index - 61
eISSN - 1440-1789
pISSN - 0919-6544
DOI - 10.1111/j.1440-1789.2000.00350.x
Subject(s) - neurodegeneration , creb , transcription factor , nuclear protein , biology , transcription (linguistics) , coactivator , microbiology and biotechnology , mutant , nuclear transport , dna binding protein , cell nucleus , genetics , gene , cytoplasm , medicine , linguistics , philosophy , disease , pathology
At least eight inherited 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. The nuclear translocation of mutant proteins containing expanded polyQ stretches has been demonstrated as 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, nuclear proteins were screened for their capability of binding to expanded polyQ stretches. It was found that expanded polyQ stretches preferentially bind to TAF II 130, a coactivator involved in cAMP‐responsive element‐binding protein (CREB)‐dependent transcriptional activation. The binding of TAF II 130 with expanded polyQ stretches strongly suppresses CREB‐dependent transcriptional activation, suggesting that interference with transcription due to the binding of expanded polyQ stretches with TAF II 130 and redistribution of TAF II 130 are involved in the pathogenetic mechanisms underlying neurodegeneration.