IngentaConnect CREB-binding protein sequestration by expanded polyglutamine

Authors: McCampbell, Alexander; Taylor, J.Paul; Taye, AddisA.; Robitschek, Jon; Li, Mei¹; Walcott, Jessica²; Merry, Diane²; Chai, Yaohui³; Paulson, Henry³; Sobue, Gen¹; Fischbeck, Kenneth H.

Source: Human Molecular Genetics, Volume 9, Number 14, 1 September 2000 , pp. 2197-2202(6)

Publisher: Oxford University Press

Abstract:

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.

Document Type: Research article

Affiliations: 1: Department of Neurology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan, 2: 208 Blumle Life Science Building, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA and 3: Department of Neurology, University of Iowa College of Medicine, 2007 RCP, Iowa City, IA 52242, USA

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