Crossing Species Barriers Relies on Structurally Distinct Prion Assemblies and Their Complementation.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Prion diseases involve the conversion of normal prion protein (PrPC) to misfolded PrPSc conformers.
• Distinct PrPSc structures can lead to different prion strains with varying biological activities.
• Prion adaptation across species is thought to involve compatibility between PrPSc templates and host PrPC.

Purpose of the Study:

• To investigate the role of PrPSc structural heterogeneity in crossing prion species barriers.
• To define the relationship between PrPSc structure, size, and biological fitness during interspecies prion transmission.

Main Methods:

• Size-fractionation of PrPSc assemblies from different prion strains.
• Transmission studies in transgenic mice expressing foreign PrPC.
• Assessment of prion pathogenesis in brain and spleen tissues.
• Analysis of specific infectivity of PrPSc assemblies.

Main Results:

• Size-fractionated PrPSc assemblies showed delayed or abrogated pathogenesis when crossing species barriers.
• This effect was independent of the initial infectivity load of the assemblies.
• Serial dilution of non-fractionated inocula reduced specific infectivity only when a species barrier was present.
• Synergy between distinct PrPSc assemblies is necessary for crossing species barriers.

Conclusions:

• Overcoming prion species barriers requires complementation between structurally distinct PrPSc assemblies.
• The 'quasispecies' concept in prions may stem from structural heterogeneity within a population, rather than solely from distinct substrains.
• Prion adaptation is influenced by the interplay of structural diversity within PrPSc assemblies.