Mutant huntingtin forms in vivo complexes with distinct context-dependent conformations of the polyglutamine segment

Huntington's disease (HD) is caused by an expanded glutamine tract, which c onfers a novel aggregation-promoting property on the 350-kDa huntingtin pro tein. Using specific antibodies, we have probed the structure of the polygl utamine segment in mutant huntingtin complexes formed in cell culture from either truncated or full-length protein, Complexes formed by a mutant amino terminal fragment most frequently entail a change in conformation that eli minates reactivity with the polyglutamine-specific mAb 1F8, coincident with production of insoluble aggregate. By contrast, complexes formed by the fu ll-length mutant protein remain soluble and are invariably 1F8-reactive, in dicating a soluble polyglutamine conformation. Therefore, aggregates in HD may form by different biochemical mechanisms that invoke different possibil ities for the pathogenic process. If pathogenesis is triggered by a truncat ed fragment, it probably involves the formation of an insoluble aggregate. However, the observation of soluble complexes in which an HD-specific patho genic conformation of the glutamine tract remains accessible suggests that pathogenesis could also be triggered at the level of full-length huntingtin by abnormal aggregation with normal or abnormal protein partners. (C) 1999 Academic Press.