Human Molecular Genetics

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Human Molecular Genetics, 2000, Vol. 9, No. 14 2197-2202
© 2000 Oxford University Press

CREB-binding protein sequestration by expanded polyglutamine

Alexander McCampbell⁺, J. Paul Taylor, Addis A. Taye, Jon Robitschek, Mei Li¹, Jessica Walcott², Diane Merry², Yaohui Chai³, Henry Paulson³, Gen Sobue¹ and Kenneth H. Fischbeck

Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10, Room 3B11, Bethesda, MD 20892-1250, USA, ¹Department of Neurology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan, ²208 Blumle Life Science Building, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA and ³Department of Neurology, University of Iowa College of Medicine, 2007 RCP, Iowa City, IA 52242, USA

Spinal and bulbar muscular atrophy (SBMA) is one of eight inherited neurodegenerative diseases known to be caused by CAG repeat expansion. The expansion 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 polyglutamine 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 inclusions formed by polyglutamine-containing proteins in cultured cells, transgenic mice and tissue from patients with SBMA. We also show CBP incorporation into nuclear inclusions formed in a cell culture model of another polyglutamine disease, spinocerebellar ataxia type 3. We present evidence that soluble levels of CBP are reduced in cells expressing expanded polyglutamine despite increased levels of CBP mRNA. Finally, we demonstrate that over-expression of CBP rescues cells from polyglutamine-mediated toxicity in neuronal cell culture. These data support a CBP-sequestration model of polyglutamine expansion disease.

⁺ To whom correspondence should be addressed. Tel: +1 301 435 9288; Fax: +1 301 480 3365; Email: mccampba@ninds.nih.gov

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