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Novel differences between two human prion strains revealed by two-dimensional gel electrophoresis

T Pan1, M Colucci, B S Wong

  • 1Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44107-1712, USA.

The Journal of Biological Chemistry
|August 8, 2001
PubMed

Insights

Prion disease phenotypes like sporadic Creutzfeldt-Jakob disease and fatal insomnia can be distinguished by differences in prion protein (PrP) glycans. These glycan alterations in PrP(Sc) suggest a novel mechanism contributing to prion diversity.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Human sporadic prion diseases exhibit diverse phenotypes influenced by prion protein (PrP) gene genotype and PrP(Sc) type.
  • Sporadic Creutzfeldt-Jakob disease (M/M2 sCJD) and sporadic fatal insomnia (sFI) share methionine homozygosity and PrP(Sc) type 2, complicating differentiation.
  • Existing methods like 1D gel electrophoresis and immunoblotting do not distinguish between M/M2 sCJD and sFI PrP(Sc).

Purpose of the Study:

  • To investigate the molecular basis for distinct phenotypes in sporadic prion diseases that share common genetic and PrP(Sc) typing characteristics.
  • To identify subtle differences in prion protein glycosylation that may contribute to prion diversity and disease phenotype.

Main Methods:

  • Utilized two-dimensional immunoblotting to analyze the prion protein (PrP) in M/M2 sCJD and sFI.
  • Compared the glycoform profiles and abundance of full-length PrP(Sc) between the two disease phenotypes.
  • Analyzed PrP(Sc) and normal cellular PrP (PrP(C)) glycosylation patterns.

Main Results:

  • Two-dimensional immunoblotting revealed differences in PrP(Sc) glycosylation between M/M2 sCJD and sFI.
  • M/M2 sCJD showed an overrepresentation of full-length PrP(Sc) with distinct glycan structures compared to sFI.
  • Altered glycans were specific to PrP(Sc), not PrP(C), suggesting preferential conversion of rare PrP(C) glycoforms.

Conclusions:

  • Qualitative differences in prion protein glycans contribute to the diversity of sporadic prion diseases.
  • Prion protein glycosylation patterns represent a novel factor in determining prion strain diversity and disease phenotype.
  • This finding opens new avenues for understanding prion pathogenesis and developing diagnostic markers.

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