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J. Biol. Chem., Vol. 279, Issue 6, 4988-4999, February 6, 2004

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Decreased cAMP Response Element-mediated Transcription

AN EARLY EVENT IN EXON 1 AND FULL-LENGTH CELL MODELS OF HUNTINGTON'S DISEASE THAT CONTRIBUTES TO POLYGLUTAMINE PATHOGENESIS^*

Katharine L. Sugars, Rosemary Brown, Lynnette J. Cook, Jina Swartz, and David C. Rubinsztein

From the Department of Medical Genetics, Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom

Huntington's disease (HD) is one of nine neurodegenerative diseases caused by an expanded polyglutamine (polyQ) tract within the disease protein. To characterize pathways induced early in HD, we have developed stable inducible PC12 cell lines expressing wild-type or mutant forms of huntingtin exon 1 fragments or the full-length huntingtin protein. Three cAMP response element-binding protein (CREB)-binding protein-dependent transcriptional pathways, regulated by cAMP response element (CRE), retinoic acid response element, and nuclear factor B, show abnormalities in our exon 1 cell model. Of these, the CRE pathway shows the earliest disruption and is significantly down-regulated as early as 12 h following mutant htt transgene induction. This pathway is also the only one of the three that is similarly perturbed in our full-length HD model, where it is also down-regulated at an early time point, compatible with observations in HD brains. Reduced CRE-dependent transcription may contribute to polyQ disease pathogenesis because overexpression of transcriptionally active CREB, but not an inactive form of the protein, is able to protect against polyQ-induced cell death and reduce aggregation.

Received for publication, September 15, 2003 , and in revised form, October 28, 2003.

^* This work was supported by grants from the Violet Richards Charity and Issac Newton Trust; the Hereditary Disease Foundation; Merck, Sharp & Dohme (to J. S); and the Medical Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

Wellcome Trust senior research fellow. To whom correspondence should be addressed. Tel.: 44-1223-762608; Fax: 44-1223-331206; E-mail: dcr1000{at}cus.cam.ac.uk.

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