Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted Journal Article uri icon
Overview
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.

  • Link to Article
    publication date
  • 2021
  • published in
    Research
    keywords
  • Genetics
  • Nervous System Diseases
  • Additional Document Info
    volume
  • 12
  • issue
  • 1