CJD and Scrapie Require Agent-Associated Nucleic Acids for Infection

Area of Science:

• Neurovirology
• Infectious Diseases
• Molecular Biology

Background:

• Transmissible Spongiform Encephalopathies (TSEs) are neurodegenerative diseases distinct from Alzheimer's.
• TSEs are caused by infectious agents, unlike other neurodegenerative diseases.
• The prevailing hypothesis attributes TSE strains to host prion protein (PrP) without genetic material.

Purpose of the Study:

• To investigate the role of nucleic acids in TSE agent infectivity.
• To challenge the prion-only hypothesis for TSE pathogenesis.
• To determine if TSE agents require genetic material for replication and transmission.

Main Methods:

• Development of rapid infectivity assays to isolate TSE particles.
• Separation of infectious particles from host components, including PrP.
• Exposure of TSE agents (FU-CJD and 22L scrapie) to nucleases in GT1 neuronal cells.

Main Results:

• Digesting PrP did not reduce brain particle titers.
• Nuclease treatment reproducibly reduced TSE agent infectivity by ≥99%.
• Protected mitochondrial and circular SPHINX DNAs were destroyed by nucleases, while PrP remained unaltered.

Conclusions:

• TSE agents require protected genetic material to infect hosts.
• These findings necessitate the reopening of investigations into essential agent nucleic acids.
• The study provides evidence against the prion-only hypothesis and supports a viral or nucleic acid-based etiology for TSEs.