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Identification of a gene regulatory network associated with prion replication

Marbiah, MM; Harvey, A; West, BT; Louzolo, A; Banerjee, P; Alden, J; Grigoriadis, A; ... Klöhn, PC; + view all (2014) Identification of a gene regulatory network associated with prion replication. The EMBO Journal , 33 (14) 1503- 1614. 10.15252/embj.201387150. Green open access

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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.

Type: Article
Title: Identification of a gene regulatory network associated with prion replication
Open access status: An open access version is available from UCL Discovery
DOI: 10.15252/embj.201387150
Publisher version: http://dx.doi.org/10.15252/embj.201387150
Language: English
Additional information: This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: Extracellular matrix, Integrin, Neurodegeneration, Prion diseases, Scrapie
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/1434068
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