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Human Molecular Genetics Advance Access originally published online on February 2, 2005
Human Molecular Genetics 2005 14(6):765-774; doi:10.1093/hmg/ddi071
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Human Molecular Genetics, Vol. 14, No. 6 © Oxford University Press 2005; all rights reserved

A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure

Michelle A. Poirier1,2,*, Haibing Jiang1,2 and Christopher A. Ross1,2,3,4

1Division of Neurobiology, 2Department of Psychiatry, 3Department of Neurology and Neuroscience and 4Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

* To whom correspondence should be addressed at: Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, 618 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205, USA. Tel:+1 410614001; Fax: +1 4106140013; Email: mpoirie1{at}jhmi.edu

Received December 15, 2004; Accepted January 24, 2005

Huntington's disease (HD) arises from an expanded polyglutamine (polyQ) in the N-terminus of the huntingtin (htt) protein. Neuronal degeneration and inclusions containing N-terminal fragments of mutant htt are present in the cortex and striatum of HD brain. Recently, a model of polyQ aggregate structure has been proposed on the basis of studies with synthetic polyQ peptides and includes an alternating beta-strand/beta-turn structure with seven glutamine residues per beta-strand. We tested this model in the context of the htt exon-1 N-terminal fragment in both mammalian cell culture and cultured primary cortical neurons. We found our data support this model in the htt protein and provide a better understanding of the structural basis of polyQ aggregation in toxicity in HD.


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