Prion Protein Deficiency Causes Diverse Proteome Shifts in Cell Models That Escape Detection in Brain Tissue

PLoS One. 2016 Jun 21;11(6):e0156779. doi: 10.1371/journal.pone.0156779. eCollection 2016.


A popular method for studying the function of a given protein is to generate and characterize a suitable model deficient for its expression. For the prion protein (PrP), best known for its role in several invariably fatal neurodegenerative diseases, a natural choice, therefore, would be to undertake such studies with brain samples. We recently documented the surprising observation that PrP deficiency caused a loss or enhancement of NCAM1 polysialylation, dependent on the cell model used. To identify possible causes for this disparity, we set out to systematically investigate the consequence of PrP deficiency on the global proteome in brain tissue and in four distinct cell models. Here we report that PrP deficiency causes robust but surprisingly divergent changes to the global proteomes of cell models but has no discernible impact on the global brain proteome. Amongst >1,500 proteins whose levels were compared in wild-type and PrP-deficient models, members of the MARCKS protein family exhibited pronounced, yet cell model-dependent changes to their steady-state levels. Follow-up experiments revealed that PrP collaborates with members of the MARCKS protein family in its control of NCAM1 polysialylation. We conclude that the physiological function of PrP may be masked in analyses of complex brain samples but its cell-type specific influence on a lipid raft-based NCAM1-related cell biology comes to the fore in investigations of specific cell types.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Brain / metabolism*
  • CD56 Antigen / metabolism
  • Calmodulin-Binding Proteins
  • Cell Line
  • Cluster Analysis
  • Gene Ontology
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kinetics
  • Membrane Proteins / metabolism
  • Mice
  • Microfilament Proteins
  • Models, Biological*
  • Myristoylated Alanine-Rich C Kinase Substrate
  • N-Acetylneuraminic Acid / metabolism
  • Prion Proteins / deficiency*
  • Prion Proteins / metabolism
  • Proteome / metabolism*
  • Proteomics
  • Reproducibility of Results
  • Sequence Homology, Amino Acid
  • Signal Transduction


  • CD56 Antigen
  • Calmodulin-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Marcks protein, mouse
  • Marcksl1 protein, mouse
  • Membrane Proteins
  • Microfilament Proteins
  • Ncam1 protein, mouse
  • Prion Proteins
  • Proteome
  • Myristoylated Alanine-Rich C Kinase Substrate
  • N-Acetylneuraminic Acid

Grants and funding

Work on this project was supported by an operating grant of the Canadian Institute for Health Research (CIHR) and an infrastructure grant from the Canadian Foundation for Innovation. The authors are most grateful to the Rosiak and Irwin families for their generous support. GS further received support from the Garfield Weston family. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.