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Protein Misfolding Cyclic Amplification of Prions
10:12

Protein Misfolding Cyclic Amplification of Prions

Published on: November 7, 2012

Y145Stop is sufficient to induce de novo generation prions using protein misfolding cyclic amplification

Ahmed Abdallah1, Ping Wang, Juergen A Richt

  • 1Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, USA.

Prion
|March 29, 2012
PubMed

Insights

A specific prion protein mutation (Y145Stop) promotes spontaneous misfolding. This truncated prion molecule, linked to Gertsmann-Sträussler-Scheincker syndrome, can convert normal prion proteins into disease-associated forms.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • A point mutation in the prion protein gene (Prnp) resulting in a truncated Y145Stop molecule is associated with Gertsmann-Sträussler-Scheincker syndrome, a type of inherited transmissible spongiform encephalopathy (TSE).
  • This truncation suggests the N-terminus (amino acids 23-144) of the prion protein is crucial for its folding and interactions.

Purpose of the Study:

  • To investigate the hypothesis that the Y145Stop prion molecule is inherently unstable and prone to misfolding.
  • To determine the role of the N-terminus (residues 23-144) in prion protein misfolding and conversion.

Main Methods:

  • Utilizing protein misfolding cyclic amplification (PMCA) to assess the in vitro conversion of recombinant prion protein fragments.
  • Comparing the misfolding propensity of the Y145Stop mutant with full-length recombinant prion protein (PrP(C)).
  • Investigating the ability of misfolded Y145Stop to convert purified normal prion protein (PrP(C)) into protease-resistant forms.

Main Results:

  • Recombinant Y145Stop polypeptide from sheep and deer PRNP converted to protease-resistant PrP(Sc) in vitro, independent of existing prions.
  • Full-length recombinant PrP(C) did not spontaneously convert to protease-resistant isoforms.
  • Misfolded Y145Stop molecules, whether seeded or spontaneous, efficiently converted purified mammalian PrP(C) into protease-resistant isoforms.

Conclusions:

  • The Y145Stop mutation creates an unstable prion protein fragment prone to spontaneous misfolding.
  • The N-terminus of the prion protein (residues 23-144) plays a significant role in the seeding and misfolding of mammalian prions.
  • These findings provide insights into the molecular mechanisms underlying inherited TSEs.

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