The Early Intermediates Revealed: the Structural Characterization of Huntingtin Exon‐1

An important question in the amyloid field is how to relate the fibril aggregation pathway to the origin of the disease. In Huntington's disease – a neurodegenerative disorder linked to mutant‐huntingtin‐exon1 aggregates – addressing the issue is crucial, as no definitive evidence exist that small mhtt‐exon1 oligomers are the neuronal toxic species rather than the mature fibrils. To unravel the mhtt‐exon1 aggregation pathway we performed time‐resolved small angle neutron scattering (TR‐SANS) with ab ‐initio reconstruction approaches. We found that pathological mhtt‐exon1 shows faster rate of aggregation, and that the structural variations of its growing intermediates are different from normal htt‐exon1 intermediates. These methods allowed us also to draw the 3‐D structures of the earliest species formed at the initial stages of aggregation. In addition, since the mass‐per length of the pathological fibrils is 4 times lower, we could determine quantitatively the differences in the internal structures of the mature aggregates. Put together, these results not only provide the first steps toward the characterization of mhtt‐exon1 aggregation pathway but also demonstrate that SANS is an essential tool for identification of various intermediates associated with amyloid and neurodegenerative diseases. NIH grant 1R21NS056325‐01A1 and the Clifford Shull Fellowship Program (ORNL) supported this research.