Enhanced neuroinvasion by smaller, soluble prions

Area of Science:

• Neuroscience
• Infectious Diseases
• Biochemistry

Background:

• Infectious prion aggregates spread from extraneural sites to the brain via peripheral nerves.
• The physical properties of prions enabling neuronal transit remain unclear.

Purpose of the Study:

• To investigate how prion conformation impacts their transit into the central nervous system (CNS).
• To determine if small, diffusible prion aggregates are responsible for spread via peripheral nerves.

Main Methods:

• Utilized a diverse panel of prion strains with varying conformations.
• Analyzed prion aggregate solubility and ultrastructure in vitro and in vivo.
• Assessed prion transport in primary neurons and in mouse models (tongue-to-brain).

Main Results:

• Subfibrillar prion strains exhibited higher solubility than fibrillar strains.
• Both strain types were internalized and transported in primary neurons, but only soluble strains efficiently traveled from tongue to brain in mice.
• Sonicating fibrillar prions increased solubility and enhanced neuroinvasion in mice.

Conclusions:

• Small, highly soluble prion particles are more efficiently transported via nerves.
• Prion solubility, not just conformation, is critical for neuroinvasion.
• Promoting prion fibril assembly may inhibit neuron-to-neuron spread.