CREB-binding protein sequestration by expanded polyglutamine

Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurode generative diseases known to be caused by CAG repeat expansion. The expansi on results in an expanded polyglutamine tract, which likely confers a novel , toxic function to the affected protein. Cell culture and transgenic mouse studies have implicated the nucleus as a site for pathogenesis, suggesting that a critical nuclear factor or process is disrupted by the polyglutamin e expansion, In this report we present evidence that CREB-binding protein ( CBP), a transcriptional co-activator that orchestrates nuclear response to a variety of cell signaling cascades, is incorporated into nuclear inclusio ns formed by polyglutamine-containing proteins in cultured cells, transgeni c mice and tissue from patients with SBMA. We also show CBP incorporation i nto nuclear inclusions formed in a cell culture model of another polyglutam ine disease, spinocerebellar ataxia type 3, We present evidence that solubl e levels of CBP are reduced in cells expressing expanded polyglutamine desp ite increased levels of CBP mRNA, Finally, we demonstrate that over-express ion of CBP rescues cells from polyglutamine-mediated toxicity in neuronal c ell culture, These data support a CBP-sequestration model of polyglutamine expansion disease.