A compact β model of huntingtin toxicity

Qi Charles Zhang, Tzu Lan Yeh, Alfonso Leyva, Leslie G. Frank, Jason Miller, Yujin E. Kim, Ralf Langen, Steven Finkbeiner, Mario L Amzel, Christopher A Ross, Michelle A. Poirier

Research output: Contribution to journalArticle


Huntington disease results from an expanded polyglutamine region in the N terminus of the huntingtin protein. HD pathology is characterized by neuronal degeneration and protein inclusions containing N-terminal fragments of mutant huntingtin. Structural information is minimal, though it is believed that mutant huntingtin polyglutamine adopts β structure upon conversion to a toxic form. To this end, we designed mammalian cell expression constructs encoding compact β variants of Htt exon 1 N-terminal fragment and tested their ability to aggregate and induce toxicity in cultured neuronal cells. In parallel, we performed molecular dynamics simulations, which indicate that constructs with expanded polyglutamine β-strands are stabilized by main-chain hydrogen bonding. Finally, we found a correlation between the reactivity to 3B5H10, an expanded polyglutamine antibody that recognizes a compact β rich hairpin structure, and the ability to induce cell toxicity. These data are consistent with an important role for a compact β structure in mutant huntingtin-induced cell toxicity.

Original languageEnglish (US)
Pages (from-to)8188-8196
Number of pages9
JournalJournal of Biological Chemistry
Issue number10
Publication statusPublished - Mar 11 2011


ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Zhang, Q. C., Yeh, T. L., Leyva, A., Frank, L. G., Miller, J., Kim, Y. E., ... Poirier, M. A. (2011). A compact β model of huntingtin toxicity. Journal of Biological Chemistry, 286(10), 8188-8196. https://doi.org/10.1074/jbc.M110.192013