A Compact β Model of huntingtin Toxicity

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 beta structure upon conversion to a toxic form. To this end, we designed mammalian cell expression constructs encoding compact beta 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 beta-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 beta rich hairpin structure, and the ability to induce cell toxicity. These data are consistent with an important role for a compact beta structure in mutant huntingtin-induced cell toxicity.