Journal Article

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

Michelle A. Poirier, Haibing Jiang and Christopher A. Ross

in Human Molecular Genetics

Volume 14, issue 6, pages 765-774
Published in print March 2005 | ISSN: 0964-6906
Published online February 2005 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddi071
A structure-based analysis of huntingtin mutant polyglutamine aggregation and toxicity: evidence for a compact beta-sheet structure

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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.

Journal Article.  6327 words.  Illustrated.

Subjects: Genetics and Genomics

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