PrPSc with Seeding Activity Extensively Overlaps with Proteinase-Resistant PrPSc Rather than Infectious PrPSc

Area of Science:

• Neuroscience
• Biochemistry
• Infectious Diseases

Background:

• The disease-associated prion protein (PrPSc) converts normal prion proteins into amyloid fibrils.
• Prion seeding activity, measured by real-time quaking-induced conversion (RT-QuIC), correlates with prion infection.
• The precise relationship between prion seeding activity and infectivity remains unclear.

Purpose of the Study:

• To evaluate the temporal relationship between prion seeding dose, proteinase-resistant PrPSc (PrPres) levels, and infectious titer.
• To investigate the correlation between RT-QuIC activity and prion infectivity in a mouse model of bovine spongiform encephalopathy (BSE).

Main Methods:

• Used endpoint dilution RT-QuIC on brain homogenates from mice infected with mouse-adopted BSE (mBSE).
• Monitored prion seeding dose, PrPres levels, and infectious titer at defined intervals during the incubation period.
• Calculated doubling times (dt) for seeding dose, PrPres, and prion titer.

Main Results:

• Infectious titer plateaued by 100 days postinfection.
• Seeding dose and PrPres levels continuously increased throughout the incubation period.
• The doubling time for seeding dose more closely matched PrPres levels than prion titer.

Conclusions:

• Prion seeding activity and PrPres levels show substantial, but not complete, overlap.
• Findings suggest that not all PrPSc with seeding activity is infectious.
• Seeding activity and PrPres accumulation may precede the plateau of infectivity in prion diseases.