Abstract
The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-β fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease.
Highlights
The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity
In order to characterize the structural differences between those fibril types, we used the established conditions to generate the previously described toxic and nontoxic fibrils from Huntingtin exon-1 (HTTex1)(Q46)
In agreement with the original study, we found that the two different fibril types exhibited distinctively different circular dichroism (CD) spectra (Fig. 1a)
Summary
The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. In contrast to fibril strains found for other cross-β fibrils, these HTTex[1] fibril types can be interconverted This is because the structure of their polyQ fibril core remains unchanged. 1234567890():,; Huntington’s disease (HD) is a debilitating neurodegenerative disease caused by mutant huntingtin with an expanded polyQ region containing more than 35 consecutive Gln residues Such polyQ expansions render the huntingtin protein and its biologically occurring N-terminal fragments more aggregation prone[1]. In addition to a structural characterization, a number of other questions remain unanswered It is not known whether the different fibril types represent distinctively different strains as seen ubiquitously for other amyloid proteins. Seeding plays an important role in misfolding and aggregate formation and it is likely that several types of misfolded proteins can spread within the brain using a seeding mechanism
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