Defining the conformational features of anchorless, poorly neuroinvasive prions

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Prion diseases exhibit diverse clinical signs and structures, from aggregates to fibrils.
• The relationship between prion conformation and disease phenotype is not fully understood.
• Mice models show divergent disease pathogenesis based on prion protein anchoring (GPI-anchored vs. GPI-anchorless).

Purpose of the Study:

• To investigate how prion physical properties, specifically anchorless prions, govern disease pathogenesis.
• To biochemically characterize infectious anchorless prions after serial passage in mice.
• To understand the impact of prion structure on neuroinvasion and stability.

Main Methods:

• Passaging infectious anchorless prions in mice expressing anchorless prion protein.
• Biochemical characterization of resulting prions, including stability assays (chaotropes, heat, SDS) and enzyme digestion resistance.
• Assessment of neuroinvasion by examining prion plaque distribution in the brain and extracerebral tissues.

Main Results:

• Serial passage of anchorless prions decreased incubation period and altered biochemical properties, indicating a transmission barrier.
• Anchorless prions demonstrated weak neuroinvasion after intraperitoneal exposure, with brain plaques being rare but abundant in extracerebral sites (heart, adipose tissue).
• Anchorless prions exhibited high stability in chaotropes, heat, and SDS, and were resistant to enzyme digestion, consistent with human patient samples.

Conclusions:

• Anchorless prions comprise fibrillar and highly stable conformers.
• Both anchorless and anchored prion fibrils appear poorly neuroinvasive.
• A fibrillar prion structure is hypothesized to impede efficient central nervous system (CNS) invasion.