Intranuclear Translocation of Mutant Proteins Containing an Expanded Polyglutamine Stretch is Implicated in the Pathogenetic Mechanisms in the Polyglutamine Diseases

At least nine inherited neurodegenerative diseases are known to be caused by expanded CAG repeats encoding polyglutamine stretches. Although cytotoxicities of expanded polyglutamine stretches have been suggested, the molecular mechanisms of neurodegeneration remain unclear. We demonstrated that nuclear translocation of mutant proteins containing expanded polyglutamine 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 polyglutamine stretches, are involved in the pathogenetic mechanisms underlying neurodegeneration, we screened nuclear proteins for their ability of binding to expanded polyglutamine stretches. We found that expanded polyglutamine stretches preferentially bind to TAF_II 130, a coactivator involved in CREB-dependent transcriptional activation. The binding of TAF_II 130 with expanded polyglutamine stretches strongly suppress CREB-dependent transcriptional activation, suggesting that interference with transcription due to the binding of expanded polyglutamine stretches with TAF_II 130 and redistribution of TAF_II 130 are involved in the pathogenetic mechanisms underlying neurodegeneration