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Cofactor molecules: Essential partners for infectious prions.

Surachai Supattapone1

  • 1Department of Biochemistry and Cell Biology and Department of Medicine, Geisel School of Medicine at Dartmouth College, Hanover, NH, United States.

Progress in Molecular Biology and Translational Science
|September 22, 2020
PubMed
Summary

Infectious prions require cofactors like RNA and phosphatidylethanolamine, challenging the protein-only hypothesis. These cofactors are essential for prion infectivity and influence prion strain properties.

Keywords:
CofactorCofactor selectionMammalianPhosphatidylethanolaminePhospholipidPolyanionPrionRNASpecific infectivity

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • The protein-only hypothesis suggests prions consist solely of misfolded PrPSc.
  • Wild-type protein-only PrPSc preparations typically lack significant prion infectivity.

Purpose of the Study:

  • To investigate the role of cofactors in prion formation and infectivity.
  • To challenge the protein-only hypothesis by identifying essential non-protein components.

Main Methods:

  • Systemic biochemical approach to isolate and identify endogenous cofactor molecules.
  • Experimental manipulation of cofactor molecules to assess their impact on prion infectivity and strain properties.

Main Results:

  • Identified RNA and phosphatidylethanolamine as endogenous cofactors facilitating high-specific-infectivity prion formation.
  • Demonstrated that purified cofactor molecules restrict the strain properties of infectious prions.
  • Proposed a "cofactor selection" model to explain strain-dependent neurotropism.

Conclusions:

  • Cofactor molecules are required for the formation of wild-type infectious prions.
  • The distribution of strain-specific cofactors may determine prion neurotropism patterns.
  • The protein-only hypothesis is insufficient to explain prion infectivity and strain diversity.