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Protein Misfolding Cyclic Amplification of Prions
10:12

Protein Misfolding Cyclic Amplification of Prions

Published on: November 7, 2012

Autocatalytic self-propagation of misfolded prion protein

Jan Bieschke1, Petra Weber, Nikolaus Sarafoff

  • 1Center for Neuropathology and Prion Research, Ludwig Maximilians University of Munich, Feodor-Lynen-Strasse 23, 81377 Munich, Germany. jbiesch@scripps.edu

Proceedings of the National Academy of Sciences of the United States of America
|August 7, 2004
PubMed

Insights

Prion protein misfolding was amplified in vitro, confirming the autocatalytic cascade. However, this protein misfolding did not replicate prion infectivity, suggesting additional factors are required.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Prions are infectious agents composed of misfolded prion protein (PrPSc).
  • Prion replication is hypothesized to occur via an autocatalytic process converting cellular PrPC to PrPSc.

Purpose of the Study:

  • To scrutinize the prion hypothesis of autocatalytic protein misfolding in vitro.
  • To investigate the relationship between PrP misfolding and prion infectivity.

Main Methods:

  • Protein Misfolding Cyclic Amplification (PMCA) was used to amplify misfolded PrP in vitro.
  • Serial transmission and serial dilution experiments were conducted using hamster brain homogenate.

Main Results:

  • In vitro amplification of misfolded PrP (PrPres) was dependent on PrPC substrate and inhibited by recombinant PrP.
  • Newly formed PrPres catalyzed PrPC conversion as efficiently as authentic PrPSc, achieving a 300-fold amplification.
  • PrPres formation did not correlate with the replication of biological infectivity.

Conclusions:

  • The study confirms an autocatalytic PrP-misfolding cascade, supporting the prion hypothesis.
  • Prion infectivity replication requires factors beyond PrP-misfolding autocatalysis.

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