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Copper-induced structural conversion templates prion protein oligomerization and neurotoxicity.

Chi-Fu Yen1, Dilshan S Harischandra2, Anumantha Kanthasamy2

  • 1Department of Electrical and Computer Engineering, Iowa State University, Ames, IA 50011, USA.

Science Advances
|July 16, 2016
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Summary

Copper exposure triggers prion protein (PrP) misfolding, leading to toxic aggregates. This molecular mechanism explains how copper causes neurodegeneration in prion disease.

Keywords:
Prion proteinRT-QuICatomic force microscopecopperforce measurementsmisfoldingneurotoxicityorganotypic slice culturesprotease resistancesingle molecule fluorescence

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Prion protein (PrP) misfolding and aggregation are central to prion diseases.
  • The role of copper (Cu2+) in prion pathogenesis remains mechanistically unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of Cu(2+)-induced PrP misfolding.
  • To investigate the role of misfolded PrP in aggregate formation and neurotoxicity.

Main Methods:

  • Single-molecule fluorescence assays to monitor PrP structural changes.
  • Single-molecule force spectroscopy to quantify binding affinities.
  • Real-time quaking-induced conversion (RT-QuIC) for seeding activity.
  • Organotypic slice cultures for assessing neurotoxicity.

Main Results:

  • Cu(2+) induces PrP monomers to misfold via the disordered amino-terminal region.
  • Misfolded PrP monomers exhibit significantly higher binding affinity, promoting oligomerization.
  • Misfolded PrP acts as a seed for templated amyloid formation.
  • Misfolded PrP mediates inflammation and neuronal degeneration in brain tissue.

Conclusions:

  • Establishes a direct molecular link between copper exposure and PrP neurotoxicity.
  • Demonstrates that Cu(2+)-induced misfolding is a critical early step in prion pathogenesis.
  • Highlights the seeding potential of misfolded PrP in driving aggregate formation and subsequent neurodegeneration.