Identification of a gene regulatory network associated with prion replication. (19th May 2014)

• Record Type: Journal Article
• Authors: Marbiah, Masue M; Harvey, Anna; West, Billy T; Louzolo, Anais; Banerjee, Priya; Alden, Jack; Grigoriadis, Anita; Hummerich, Holger; Kan, Ho‐Man; Cai, Ying; Bloom, George S; Jat, Parmjit; Collinge, John; Klöhn, Peter‐Christian
• Is Part Of: EMBO journal. Volume 33:Number 14(2014)
• Page Start: 1527
• Page End: 1547
• Publication Date: 2014-05-19
• Subjects: Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201387150
• Languages: English
• ISSNs: 0261-4189

Abstract

<abstract abstract-type="main" id="embj201387150-abs-0001"> <title>Abstract</title> <p>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 <italic>Papss2</italic> 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.</p> </abstract>