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Huntington's disease protein aggregates (HTTex1 fibrils) show varying toxicity due to proline-rich domain dynamics. Less entangled, more toxic fibrils enhance protein interactions and seeding in neurodegenerative disease.

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Area of Science:

  • Biochemistry
  • Neuroscience
  • Molecular Biology

Background:

  • Huntington's disease (HD) is linked to the huntingtin protein (HTTex1) forming toxic cross-β fibrils.
  • The C-terminal proline-rich domain (PRD) of HTTex1 influences fibril structure and toxicity.

Purpose of the Study:

  • To investigate the structural basis for varying HTTex1 fibril toxicity.
  • To understand the role of PRD dynamics and entanglement in fibril formation and seeding.

Main Methods:

  • Analysis of HTTex1 fibril structures and dynamics.
  • In vitro seeding assays with recombinant HTTex1.
  • Cell-based assays to assess HTTex1 aggregation and toxicity.

Main Results:

  • HTTex1 fibrils exhibit varying toxicity correlated with PRD entanglement and dynamics.
  • Fibril strains are interconvertible, with the polyQ core structure remaining constant.
  • Less entangled, more toxic fibrils show increased affinity for protein interactors and enhanced seeding.

Conclusions:

  • PRD structure and dynamics at the fibril surface modulate seeding and protein interactions.
  • These mechanisms contribute to the toxicity of HTTex1 aggregates in neurodegenerative disease.
  • Understanding these structural variations offers insights into HD pathogenesis.