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EMBO J. 2014 Jul 17;33(14):1527-47. doi: 10.15252/embj.201387150. Epub 2014 May 19.

Identification of a gene regulatory network associated with prion replication.

Author information

1
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology Queen Square, London, UK.
2
Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
3
Biomedical Communications, Terrence Donnelly Health Sciences Complex University of Toronto, Toronto, ON, Canada.
4
Breakthrough Breast Cancer Research Unit, Research Oncology, Guy's Hospital, London, UK.
5
Department of Biology, University of Virginia, Charlottesville, VA, USA.
6
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology Queen Square, London, UK p.kloehn@prion.ucl.ac.uk.

Abstract

Prions consist of aggregates of abnormal conformers of the cellular prion protein (PrP(C)). They propagate by recruiting host-encoded PrP(C) although the critical interacting proteins and the reasons for the differences in susceptibility of distinct cell lines and populations are unknown. We derived a lineage of cell lines with markedly differing susceptibilities, unexplained by PrP(C) expression differences, to identify such factors. Transcriptome analysis of prion-resistant revertants, isolated from highly susceptible cells, revealed a gene expression signature associated with susceptibility and modulated by differentiation. Several of these genes encode proteins with a role in extracellular matrix (ECM) remodelling, a compartment in which disease-related PrP is deposited. Silencing nine of these genes significantly increased susceptibility. Silencing of Papss2 led to undersulphated heparan sulphate and increased PrP(C) deposition at the ECM, concomitantly with increased prion propagation. Moreover, inhibition of fibronectin 1 binding to integrin α8 by RGD peptide inhibited metalloproteinases (MMP)-2/9 whilst increasing prion propagation. In summary, we have identified a gene regulatory network associated with prion propagation at the ECM and governed by the cellular differentiation state.

KEYWORDS:

extracellular matrix; integrin; neurodegeneration; prion diseases; scrapie

PMID:
24843046
PMCID:
PMC4198050
DOI:
10.15252/embj.201387150
[Indexed for MEDLINE]
Free PMC Article
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