Early existence and biochemical evolution characterise acutely synaptotoxic PrPSc

Area of Science:

• Neuroscience
• Prion Biology
• Molecular Pathology

Background:

• Misfolded prion protein (PrPSc) is central to prion diseases, but the timing of neurotoxic species emergence is unclear.
• Understanding PrPSc pathogenesis is crucial for developing effective treatments.

Purpose of the Study:

• To determine the earliest time point of acute synaptotoxicity of PrPSc during prion disease progression.
• To characterize the biochemical properties of synaptotoxic PrP species.

Main Methods:

• Electrophysiology assessed acute synaptotoxicity of PrPSc from M1000 infected mouse brains at various disease stages (30%, 50%, 70%, 100% TSD).
• Synaptotoxicity measured by impairment of hippocampal long-term potentiation (LTP) and post-tetanic potentiation (PTP).
• PrP species were analyzed using immuno-depletion, size fractionation chromatography, and enhanced sensitivity western blotting with proteinase K (PK) digestion.

Main Results:

• PrPSc from 30% of the terminal stage of disease (TSD) significantly impaired LTP and PTP.
• Synaptotoxicity correlated with oligomeric PrP species, peaking around 50% TSD.
• Early synaptotoxic PrPSc species (up to 70% TSD) were proteinase-sensitive, while PK-resistant PrPSc increased later.

Conclusions:

• Synaptotoxic and infectious PrPSc species emerge concurrently by at least 30% TSD.
• These species increase during disease progression, with proteinase-sensitive oligomers being key early contributors.
• Findings provide critical insights into the early pathogenesis of prion diseases.