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Screening for Amyloid Aggregation by Semi-Denaturing Detergent-Agarose Gel Electrophoresis
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Published on: July 16, 2008

Codon 129 polymorphism of the human prion protein influences the kinetics of amyloid formation

Patrick A Lewis1, M Howard Tattum1, Samantha Jones1

  • 1MRC Prion Unit, Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.

The Journal of General Virology
|July 19, 2006
PubMed

Insights

The common 129 polymorphism in human prion protein (PrP) affects amyloid fibril formation in partially denatured states, not native structure or copper binding. This finding is crucial for understanding prion disease mechanisms.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Structural Biology

Background:

  • The human prion protein (PrP) exhibits a common polymorphism at residue 129, with either valine or methionine.
  • This polymorphism significantly impacts susceptibility to prion diseases and influences prion strain characteristics.

Purpose of the Study:

  • To investigate the effect of the PrP 129 polymorphism on protein structure and function.
  • To determine if the polymorphism influences the conversion to beta-PrP conformation, copper(II) ion binding, or amyloid fibril formation.

Main Methods:

  • Comparative analysis of PrP variants with different residue 129 polymorphisms.
  • Assessment of native PrP structure.
  • Evaluation of conversion efficiency to beta-PrP conformation.
  • Measurement of copper(II) ion binding.
  • In vitro studies on spontaneous amyloid fibril formation under partially denaturing conditions.

Main Results:

  • The 129 polymorphism does not alter the native structure of cellular PrP (PrPC).
  • The amino acid variation at residue 129 does not affect the efficiency of conversion to the beta-PrP conformation.
  • Copper(II) ion binding affinity remains unchanged by the polymorphism.
  • A significant influence of the 129 polymorphism on spontaneous amyloid fibril formation was observed in partially denatured PrP.

Conclusions:

  • The PrP 129 polymorphism critically affects amyloidogenesis in partially denatured states, despite having no impact on native structure or key biochemical interactions.
  • These findings highlight the conformational flexibility of PrP and the specific role of the 129 polymorphism in disease-relevant aggregation pathways.

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