Prion Disease Mechanisms and Diagnostics

Prion diseases are fatal neurodegenerative disorders characterised by the conversion of the normal cellular prion protein (PrPC) into a misfolded, β-sheet-rich isoform (PrPSc) that aggregates into amyloid fibrils. This self-propagating conformational change underlies neuronal dysfunction, spongiform degeneration and gliosis. Mechanistically, prion propagation involves templated protein misfolding, strain‐specific conformations and cell-to-cell spread. Recent insights reveal non-cell-autonomous interactions in which glial subtypes modulate neurotoxicity and inflammatory mediators amplify neuronal loss. Strain diversity arises from distinct folding subdomains within PrP fibrils, explaining variability in incubation times, regional pathology and species barriers. Diagnostics have advanced from clinical observation and neuropathology to ultrasensitive assays that detect seeding activity in bodily fluids. Real-time quaking-induced conversion (RT-QuIC) and related techniques exploit the ability of PrPSc seeds to nucleate recombinant PrP into detectable amyloid, while emerging fluid biomarkers such as glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) provide quantitative measures of ongoing neurodegeneration. Together, mechanistic understanding and novel diagnostics offer pathways to earlier detection, patient stratification and targeted therapeutic interventions.

Research from Nature Portfolio

Recent studies have uncovered a neuroprotective role for oligodendrocyte-lineage (NG2) glia in prion disease. Upon infection, NG2 glia moderate microglial synthesis of prostaglandin E2 (PGE2), limiting downstream EP4 receptor–mediated neurotoxicity. Pharmacological or genetic blockade of PGE2 biosynthesis attenuates neuronal loss in organotypic cerebellar slices and extends survival in prion-inoculated mice, highlighting a glia-to-glia signalling axis as an actionable target.

High-resolution cryogenic electron microscopy of infectious prion fibrils from distinct mouse strains has defined the parallel in-register intermolecular β-sheet architecture and identified strain-specific folding subdomains. Comparison of ME7 and RML fibrils at near-atomic resolution reveals how subtle sequence differences direct alternative packing arrangements within PrP rungs, providing a structural basis for intra-species strain diversity and advancing understanding of prion conformer heterogeneity.

Prion Disease Mechanisms and Diagnostics publication trend

The graph below shows the total number of articles in prion disease mechanisms and diagnostics across all publications each year (not limited to Nature Index journals).

Technical terms

PrPC: The normal, α-helical cellular prion protein expressed on the surface of neurons and other cell types.

PrPSc: The misfolded, aggregation-prone isoform of prion protein that seeds conversion of PrPC and forms infectious amyloid.

RT-QuIC: Real-time quaking-induced conversion assay that amplifies minute amounts of prion seeds into detectable amyloid fibrils using recombinant PrP substrates.

GFAP: Glial fibrillary acidic protein, an intermediate filament protein released by reactive astrocytes and measurable in biofluids as a marker of neuroinflammation.

NfL: Neurofilament light chain, a cytoskeletal protein of neurons that enters CSF and blood upon axonal damage, serving as a quantitative neurodegeneration biomarker.

References

1. NG2 glia protect against prion neurotoxicity by inhibiting microglia-to-neuron prostaglandin E2 signaling. Nature Neuroscience (2024).
2. A structural basis for prion strain diversity. Nature Chemical Biology (2023).
3. Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease. Brain (2023).
4. Rapid End-Point Quantitation of Prion Seeding Activity with Sensitivity Comparable to Bioassays. PLOS Pathogens (2010).
5. Bank Vole Prion Protein As an Apparently Universal Substrate for RT-QuIC-Based Detection and Discrimination of Prion Strains. PLOS Pathogens (2015).