A linear lattice model for polyglutamine in CAG-expansion diseases

Huntington's disease and several other neurological diseases are caused by expanded polyglutamine [poly(Gin)] tracts in different proteins. Mechanisms for expanded (>36 Gin residues) poly(Gin) toxicity include the formation of aggregates that recruit and sequester essential cellular proteins [Preisinger, E., Jordan, B. M., Kazantsev, A. & Housman, D. (1999) Phil. Trans. R. Soc. London B 354,1029-1034; Chen, S., Berthelier, V., Yang, W. & Wetzel, R. (2001) J. Mol .Biol. 311, 173-182] and functional alterations, such as improper interactions with other proteins [Cummings, C. J. & Zoghbi, H. Y. (2000) Hum. MoL Genet 9,909-916]. Expansion above the pathologic threshold (approximate to36 Gin) has been proposed to induce a conformational transition in poly(Gin) tracts, which has been suggested as a target for therapeutic intervention. Here we show that structural analyses of soluble huntingtin exon 1 fusion proteins with 16 to 46 glutamine residues reveal extended structures with random coil characteristics and no evidence for a global conformational change above 36 glutamines. An antibody (MW1) Fab fragment, which recognizes full-length huntingtin in mouse brain sections, binds specifically to exon 1 constructs containing normal and expanded poly(Gin) tracts, with affinity and stoichiometry that increase with poly(Gin) length. These data support a linear lattice model for poly(Gin), in which expanded poly(Gin) tracts have an increased number of ligand-binding sites as compared with normal poly(Gin). The linear lattice model provides a rationale for pathogenicity of expanded poly(Gin) tracts and a structural framework for drug design.