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Protein Misfolding Cyclic Amplification of Prions
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Published on: November 7, 2012

Prion processing: a double-edged sword?

Hilary E M McMahon1

  • 1UCD School of Biomolecular and Biomedical Science, Conway Institute for Biomolecular and Biomedical Research University College Dublin, Belfield, Dublin 4, Ireland. hilary.mcmahon@ucd.ie

Biochemical Society Transactions
|July 24, 2012
PubMed
Summary
This summary is machine-generated.

Cellular prion protein (PrP(C)) degradation involves two cleavages: α-cleavage, which prevents prion disease, and β-cleavage, which combats oxidative stress but may also promote disease. Understanding these processes is key to prion disease research.

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Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans

Published on: January 8, 2015

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Cellular prion protein (PrP(C)) undergoes proteolytic cleavage, generating fragments with roles in normal function and disease.
  • Two primary cleavage events, α-cleavage and β-cleavage, occur in the N-terminus of PrP(C).
  • Prion diseases are linked to the misfolding and aggregation of PrP(C) into the abnormal PrP(Sc) isoform.

Purpose of the Study:

  • To elucidate the distinct roles of α-cleavage and β-cleavage in PrP(C) metabolism.
  • To investigate the impact of β-cleavage, induced by reactive oxygen species (ROS), on prion disease pathogenesis.
  • To understand how PrP(C) processing influences oxidative stress and prion conversion.

Main Methods:

  • Analysis of PrP(C) cleavage sites and resulting fragments.
  • Investigation of the enzymatic activity and functional consequences of α-cleavage.
  • Characterization of β-cleavage induced by ROS and its relationship to PrP(Sc) formation.

Main Results:

  • α-Cleavage at residues 110-111 of PrP(C) inhibits the conversion to the disease-associated PrP(Sc) isoform.
  • β-Cleavage, mediated by ROS, produces a C2 fragment that may seed PrP(Sc) formation.
  • Evidence suggests β-cleavage also serves a crucial role in mitigating oxidative stress.

Conclusions:

  • PrP(C) cleavage pathways present a complex interplay between neuroprotection and prion disease progression.
  • β-Cleavage acts as a double-edged sword, potentially reducing ROS while also facilitating prion conversion.
  • Targeting these cleavage events could offer novel therapeutic strategies for prion-related disorders.