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Prion permissive pathways: extracellular matrix genes control susceptibility to prion infection
- Source :
- The EMBO Journal
- Publication Year :
- 2014
- Publisher :
- EMBO, 2014.
-
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.
- Subjects :
- Models, Molecular
Prions
integrin
animal diseases
extracellular matrix
Cellular differentiation
Gene regulatory network
Biology
Real-Time Polymerase Chain Reaction
General Biochemistry, Genetics and Molecular Biology
Transcriptome
Extracellular matrix
Mice
Prion infection
Animals
Humans
Gene Regulatory Networks
PrPC Proteins
Cloning, Molecular
RNA, Small Interfering
Permissive
Molecular Biology
Gene
General Immunology and Microbiology
General Neuroscience
scrapie
neurodegeneration
Cell Differentiation
Articles
Flow Cytometry
Microarray Analysis
prion diseases
nervous system diseases
Fungal prion
Cell biology
Have You Seen?
Microscopy, Fluorescence
Spectrophotometry
ras GTPase-Activating Proteins
Subjects
Details
- ISSN :
- 14602075 and 02614189
- Volume :
- 33
- Database :
- OpenAIRE
- Journal :
- The EMBO Journal
- Accession number :
- edsair.doi.dedup.....e76f8b0371034b97133f4b5bd803349d