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Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
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Anchorless prion protein results in infectious amyloid disease without clinical scrapie

Bruce Chesebro1, Matthew Trifilo, Richard Race

  • 1Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, MT 59840, USA. bchesebro@niaid.nih.gov

Science (New York, N.Y.)
|June 4, 2005
PubMed

Insights

The prion protein's GPI anchor influences prion disease. Amyloid plaques from anchorless PrP caused brain damage but minimal symptoms, while combined anchorless and wild-type PrP accelerated disease.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • The roles of amyloid and nonamyloid deposits in prion and Alzheimer's diseases are unclear.
  • Prion protein (PrP) aggregation is central to prion diseases.

Purpose of the Study:

  • To investigate the role of the prion protein's glycosylphosphatidylinositol (GPI) anchor in prion disease pathogenesis.
  • To determine if anchorless PrP aggregation into amyloid plaques affects disease characteristics.

Main Methods:

  • Generated transgenic mice expressing anchorless PrP.
  • Infected mice with scrapie agent.
  • Analyzed PrP deposition (amyloid vs. nonamyloid) and clinical signs.

Main Results:

  • Anchorless PrP formed abnormal protease-resistant PrPres deposits as amyloid plaques.
  • These amyloid plaques induced brain damage similar to Alzheimer's disease but with minimal clinical manifestations.
  • Combined expression of anchorless and wild-type PrP led to accelerated clinical scrapie.

Conclusions:

  • The GPI anchor of PrP may be crucial for the typical pathogenesis of prion diseases.
  • Amyloid plaque formation by anchorless PrP can cause neuropathology without severe clinical symptoms.
  • Modulating PrP GPI anchor expression could be a therapeutic target for prion disorders.

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