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Updated: Jun 5, 2025

Protein Misfolding Cyclic Amplification of Prions
10:12

Protein Misfolding Cyclic Amplification of Prions

Published on: November 7, 2012

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Chaperone-mediated disaggregation of infectious prions releases particles that seed new prion formation in a

Daniel Shoup1, Suzette A Priola1

  • 1Rocky Mountain Laboratories, Laboratory of Neurological Infections and Immunity, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA.

The Journal of Biological Chemistry
|December 11, 2024
PubMed

Insights

Molecular chaperones like Grp78 and Hsp110 can break down infectious prion protein aggregates (PrPD). This disassembly releases active prion seeds in a strain-specific manner, potentially aiding prion disease spread.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Mammalian prion protein (PrPC) misfolds into infectious aggregates (PrPD), causing fatal prion diseases.
  • Molecular chaperones, like Grp78, are involved in protein refolding and degradation.
  • Previous studies showed Grp78 sensitizes PrPD to proteases, but chaperone-mediated disaggregation and its effect on prion seeding remain unclear.

Purpose of the Study:

  • To investigate chaperone-mediated disaggregation of PrPD from different prion strains.
  • To determine the role of Hsp110 disaggregase family members (Hsp105, Apg-2) in PrPD structural modification and disaggregation.
  • To assess the seeding activity of PrPD aggregates after chaperone-mediated disassembly.

Main Methods:

  • Studied PrPD structural modification, disaggregation, and seeding activity using two mouse-adapted prion strains (22L and 87V).
  • Utilized Grp78 and two Hsp110 disaggregase family members (Hsp105, Apg-2) in chaperone-mediated disaggregation assays.
  • Analyzed protease resistance and seeding potential of disaggregated PrPD.

Main Results:

  • Both Hsp105 and Apg-2 induced similar disaggregation and structural changes in PrPD cores.
  • The 22L prion strain PrPD was more susceptible to chaperone-induced destabilization and disaggregation than the 87V strain.
  • Despite disaggregation, only 22L PrPD released by chaperones retained seeding activity, with Hsp110 enhancing Grp78-mediated release.

Conclusions:

  • Grp78 and Hsp110 chaperones can disassemble PrPD aggregates.
  • Chaperone-mediated disassembly releases PrPD seeding particles in a strain-specific manner.
  • This process may contribute to prion replication and the spread of prion diseases.
Keywords:
Apg-2Grp78Hsp105Hsp110RT-QuICchaperonemolecular chaperoneprionprion diseaseprotein aggregationprotein stabilityseeding activity

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