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

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.