Novel Proteinaceous Infectious Particles Cause Scrapie

Author: Stanley B. Prusiner Year: 1982 Source: Science, Vol. 216, No. 4542, pp. 136-144 DOI: 10.1126/science.6801762

Overview

In this landmark paper, Stanley Prusiner introduces the term “prion” to describe the infectious agent causing scrapie, a degenerative neurological disorder in sheep and goats. He provides evidence that the agent is primarily composed of protein and lacks a detectable nucleic acid genome, challenging the “central dogma” of molecular biology which states that all infectious agents must contain DNA or RNA.

Core Argument

The scrapie agent is a “proteinaceous infectious particle” (prion) that is resistant to most procedures that modify nucleic acids (e.g., UV radiation, nucleases) but is inactivated by treatments that denature or modify proteins (e.g., proteases, SDS, diethylpyrocarbonate). The agent’s unique properties distinguish it from viruses, viroids, and plasmids.

Key Findings

Resistance to Nucleic Acid Inactivation

  • Finding: The scrapie agent remains infectious after exposure to high doses of UV radiation (254 nm) and treatment with various nucleases (ribonucleases, deoxyribonucleases).
  • Argument: If the agent contained a functional nucleic acid genome, these treatments would significantly reduce its infectivity. The observed resistance suggests that the agent is either devoid of nucleic acid or its nucleic acid is extremely well-protected and very small.
  • Strength of Evidence: Strong (multiple independent methods of nucleic acid modification failed to inactivate the agent).

Sensitivity to Protein Modification

  • Finding: Infectivity is significantly reduced or eliminated by procedures that denature or chemically modify proteins, including treatment with proteinase K, trypsin, sodium dodecyl sulfate (SDS), urea, and phenol.
  • Argument: The loss of infectivity upon protein denaturation demonstrates that a protein component is essential for the agent’s ability to replicate and cause disease.
  • Strength of Evidence: Strong (consistent results across various protein-modifying treatments).

Small Molecular Size

  • Finding: Target size analysis using ionizing radiation and molecular sieve chromatography suggests a molecular weight for the infectious unit of approximately 50,000 daltons or less.
  • Argument: This size is too small to encode a protein of its own size if it were a conventional virus with a nucleic acid genome.
  • Strength of Evidence: Moderate (based on indirect measurements).

Lack of Immunogenicity

  • Finding: Extensive efforts to raise antibodies against the scrapie agent in its native form have been unsuccessful.
  • Argument: This may indicate that the prion protein is closely related to a normal host protein, leading to immunological tolerance.
  • Strength of Evidence: Moderate (observational).

Mechanisms Proposed

Prion Replication Hypotheses

Prusiner discusses several hypothetical models for how a protein-only agent could replicate:

  1. Undetected Nucleic Acid: The prion contains a very small, highly protected nucleic acid that codes for its protein(s).
  2. Reverse Translation: Information is transferred from protein to RNA or DNA (highly unorthodox and contradicts the central dogma).
  3. Protein-Directed Protein Synthesis: The prion protein directs the synthesis of more of itself (also contradicts central dogma).
  4. Host-Encoded Prion: The host genome contains the gene for the prion protein, and the infectious agent triggers its expression or post-translational modification from a normal precursor to the pathological form.

What this paper adds

This paper formalizes the prion hypothesis and provides a comprehensive experimental basis for the existence of infectious agents lacking nucleic acids. It shifted the search for the scrapie agent from virology to protein chemistry and provided a new framework for understanding other “slow virus” diseases like Creutzfeldt-Jakob disease (CJD) and kuru.

Limitations and Caveats

  • The precise chemical structure of the prion was not yet determined.
  • The possibility of a small, well-hidden nucleic acid could not be definitively excluded with 100% certainty at the time.
  • The mechanisms of replication were speculative.

Open Questions

  • What is the molecular structure of the prion protein?
  • Is the prion protein encoded by a host gene?
  • How exactly does the prion cause neuronal vacuolation and death?
  • Do prions play an etiological role in other degenerative diseases like Alzheimer’s or Parkinson’s?

How this updates or contradicts existing wiki pages

  • Alzheimer’s Disease: Prusiner mentions that prions might be involved in Alzheimer’s (as a “slow virus” candidate), which connects to early theories of AD etiology.
  • Creutzfeldt-Jakob Disease (CJD): Links CJD, kuru, and scrapie as part of a common family of transmissible spongiform encephalopathies (TSEs).