Formation and Structure of Wild Type Huntingtin Exon‑1 Fibrils

The fact that the heritable neurodegenerative disorder Huntington’s disease (HD) is autosomal dominant means that there is one wild type and one mutant allele in most HD patients. The CAG repeat expansion in the exon 1 of the protein huntingtin (HTT_ex1) that causes the disease leads to the formation of HTT fibrils in vitro and vivo. An important question for understanding the molecular mechanism of HD is which role wild type HTT plays for the formation, propagation, and structure of these HTT fibrils. Here we report that fibrils of mutant HTT_ex1 are able to seed the aggregation of wild type HTT_ex1 into amyloid fibrils, which in turn can seed the fibril formation of mutant HTT_ex1. Solid-state NMR and electron paramagnetic resonance data showed that wild type HTT_ex1 fibrils closely resemble the structure of mutant fibrils, with small differences indicating a less extended fibril core. These data suggest that wild type fibrils can faithfully perpetuate the structure of mutant fibrils in HD. However, wild type HTT_ex1 monomers have a much higher equilibrium solubility compared to mutant HTT_ex1, and only a small fraction incorporates into fibrils.