At least eight inherited neurodegenerative diseases are caused by expanded CAG repeats encoding polyglutamine (polyQ) stretches. Although cytotoxicities of expanded polyQ stretches are implicated, the molecular mechanisms of neurodegeneration remain unclear. We found that expanded! polyQ stretches preferentially bind to TAF(II)130, a coactivator involved in cAMP-responsive element binding protein (CREB)-dependent transcriptional activation, and strongly suppress CREB-dependent transcriptional activation. The suppression of CREB-dependent transcription and the cell death induced by polyQ stretches were restored by the co-expression of TAF(II)130. Our results indicate that interference of transcription by the binding of TAF(II)130 with expanded polyQ stretches is involved in the pathogenetic mechanisms underlying neurodegeneration.