Display Settings:

Format

Send to:

Choose Destination
Prion. 2014 Jan 8;8(1). [Epub ahead of print]

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

Author information

  • 1Department of Pathology; School of Medicine; Case Western Reserve University; Cleveland, OH USA.
  • 2Department of Pathology; School of Medicine; Case Western Reserve University; Cleveland, OH USA; Department of Neurology; School of Medicine; Case Western Reserve University; Cleveland, OH USA.

Abstract

There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrPC) to a misfolded pathogenic conformer (PrPSc). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrPSc. Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrPSc particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrPSc conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrPSc conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrPSc. Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and adapt by a prion-like mechanism calls for the reevaluation of therapeutic strategies that target aggregates of misfolded proteins, and argues for new therapeutic approaches that will focus on prior pathogenetic steps.

KEYWORDS:

conformational evolution; human PrPSc coexistence; neurodegeneration; prion strains; sporadic Creutzfeldt-Jakob disease (sCJD)

PMID:
24401672
[PubMed - as supplied by publisher]
Free full text
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Icon for Landes Bioscience
    Loading ...
    Write to the Help Desk