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Human Molecular Genetics, 2003, Vol. 12, No. 1 1-12
© 2003 Oxford University Press

Cell death triggered by polyglutamine-expanded huntingtin in a neuronal cell line is associated with degradation of CREB-binding protein

Haibing Jiang1, Frederick C. Nucifora, Jr3, Christopher A. Ross3 and Donald B. DeFranco1,2,*

1Department of Pharmacology and 2Department of Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA and 3Laboratory of Molecular Neurobiology, Department of Psychiatry and Neuroscience, The Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine Baltimore, MD 21205, USA

Received July 10, 2002; Revised October 10, 2002; Accepted October 30, 2002

Huntington's Disease belongs to the CAG repeat family of neurodegenerative diseases and is characterized by the presence of an expanded polyglutamine (polyQ) repeat in the huntingtin (htt) gene product. PolyQ-expanded htt accumulates within large aggregates that are found in various subcellular compartments, but are more often localized within the nucleus. It has been suggested that the sequestration of proteins essential to cell viability may be one mechanism that accounts for toxicity generated by polyQ-expanded proteins. Nuclear inclusions containing polyQ-expanded htt recruit the transcriptional cofactor, CREB-binding protein (CBP). PolyQ toxicity appears to involve alterations of gene transcription and reduced neuronal cell viability. In the HT22 hippocampal cell line, we find that toxicity within individual cells induced by polyQ-expanded htt, as revealed by a TUNEL assay, is associated with the localization of the mutant htt within either nuclear or perinuclear aggregates. However, in addition to CBP recruitment, we show here that CBP ubiquitylation and degradation can be selectively enhanced by polyQ-expanded htt. Thus, selected substrates may be directed to the ubiquitin/proteasome-dependent protein degradation pathway in response to polyQ-expanded htt within the nucleus.

* To whom correspondence should be addressed. Tel: +1 4126244259; Fax: +1 4126481945; Email: dod1{at}pitt.edu


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