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Membrane-anchored PrPSc is the trigger for prion synaptotoxicity.

Jean R P Gatdula1, Robert C C Mercer1, Jose Andres Alepuz Guillen1

  • 1Department of Biochemistry and Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, United States of America.

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Prion diseases involve toxic protein (PrPSc) signaling that damages synapses. This study found that newly formed PrPSc on neuronal surfaces triggers this damage, suggesting G126V PrP mutations may offer a therapeutic strategy against prion diseases.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Prion diseases are characterized by neuropathological damage caused by prions (PrPSc).
  • A known synaptotoxic pathway involves extracellular PrPSc stimulating NMDA receptors, leading to synaptic dysfunction.
  • It remains unclear if this pathway is directly linked to PrPC-to-PrPSc conversion or can be initiated independently.

Purpose of the Study:

  • To investigate whether synaptotoxic signaling in prion diseases requires de novo PrPSc formation at the neuronal surface.
  • To determine if extracellular PrPSc can initiate synaptotoxicity independently of PrPC conversion.
  • To explore the therapeutic potential of mutations that inhibit PrPC-PrPSc conversion.

Main Methods:

  • Utilized neuronal expression of PrPC mutants (G126V, V208M) resistant to conversion.
  • Applied heterologous PrPSc to neurons expressing homologous PrPC to block conversion.
  • Assessed synaptotoxicity by quantifying dendritic spine density in primary hippocampal neurons after prion exposure.

Main Results:

  • PrPC mutants G126V and V208M significantly impaired or blocked PrPC-PrPSc conversion.
  • Expression of G126V PrP completely prevented spine retraction across multiple prion strains.
  • Inter-species PrPC expression attenuated spine retraction, indicating a requirement for homologous conversion.

Conclusions:

  • Newly formed PrPSc at the neuronal surface is essential for initiating prion-mediated synaptotoxic signaling.
  • Synaptotoxicity does not appear to be initiated by extracellular PrPSc independently of conversion.
  • The G126V PrP mutation shows promise as a therapeutic strategy to inhibit PrPSc conversion in prion diseases.