eprintid: 1434068 rev_number: 41 eprint_status: archive userid: 608 dir: disk0/01/43/40/68 datestamp: 2014-07-07 20:40:51 lastmod: 2021-09-19 23:23:33 status_changed: 2014-07-07 20:40:51 type: article metadata_visibility: show item_issues_count: 0 creators_name: Marbiah, MM creators_name: Harvey, A creators_name: West, BT creators_name: Louzolo, A creators_name: Banerjee, P creators_name: Alden, J creators_name: Grigoriadis, A creators_name: Hummerich, H creators_name: Kan, HM creators_name: Cai, Y creators_name: Bloom, GS creators_name: Jat, P creators_name: Collinge, J creators_name: Klöhn, PC title: Identification of a gene regulatory network associated with prion replication ispublished: pub divisions: UCL divisions: B02 divisions: C07 divisions: DF9 divisions: FA5 keywords: Extracellular matrix, Integrin, Neurodegeneration, Prion diseases, Scrapie note: 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. 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. date: 2014-05-19 official_url: http://dx.doi.org/10.15252/embj.201387150 vfaculties: VFBRS oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: JOURNAL ARTICLE verified: verified_manual elements_source: PubMed elements_id: 949462 doi: 10.15252/embj.201387150 pii: embj.201387150 language_elements: ENG lyricists_name: Collinge, John lyricists_name: Hummerich, Holger lyricists_name: Jat, Parmjit lyricists_name: Kloehn, Peter-Christian lyricists_id: JCOLL20 lyricists_id: HHUMM25 lyricists_id: PSJAT07 lyricists_id: PKLOE55 full_text_status: public publication: The EMBO Journal volume: 33 number: 14 pagerange: 1503- 1614 issn: 1460-2075 citation: Marbiah, MM; Harvey, A; West, BT; Louzolo, A; Banerjee, P; Alden, J; Grigoriadis, A; ... Klöhn, PC; + view all <#> Marbiah, MM; Harvey, A; West, BT; Louzolo, A; Banerjee, P; Alden, J; Grigoriadis, A; Hummerich, H; Kan, HM; Cai, Y; Bloom, GS; Jat, P; Collinge, J; Klöhn, PC; - view fewer <#> (2014) Identification of a gene regulatory network associated with prion replication. The EMBO Journal , 33 (14) 1503- 1614. 10.15252/embj.201387150 <https://doi.org/10.15252/embj.201387150>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/1434068/1/1527.full.pdf