A hallmark of polyglutamine diseases, including Huntington disease (HD), is the formation of β-sheet-rich aggregates, called amyloid, of causative proteins with expanded polyglutamines. However, it has remained unclear whether the polyglutamine amyloid is a direct cause or simply a secondary manifestation of the pathology. Here we show that huntingtin-exon1 (thtt) with expanded polyglutamines remarkably misfolds into distinct amyloid conformations under different temperatures, such as 4 °C and 37 °C. The 4 °C amyloid has loop/turn structures together with mostly β-sheets, including exposed polyglutamines, whereas the 37 °C amyloid has more extended and buried β-sheets. By developing a method to efficiently introduce amyloid into mammalian cells, we found that the formation of the 4 °C amyloid led to substantial toxicity, whereas the toxic effects of the 37 °C amyloid were very small. Importantly, thtt amyloids in different brain regions of HD mice also had distinct conformations. The thermolabile thtt amyloid with loop/turn structures in the striatum showed higher toxicity, whereas the rigid thtt amyloid with more extended β-sheets in the hippocampus and cerebellum had only mild toxic effects. These studies show that the thtt protein with expanded polyglutamines can misfold into distinct amyloid conformations and, depending on the conformations, the amyloids can be either toxic or nontoxic. Thus, the amyloid conformation of thtt may be a critical determinant of cytotoxicity in HD.

Nekooki-Machida, Y., Kurosawa, M., Nukina, N., Ito, K., Oda, T., & Tanaka, M. (2009). Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. Proceedings of the National Academy of Sciences, 106(24), 9679–9684.