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Identification of a gene regulatory network associated with prion replication.

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.

SUBMITTER: Marbiah MM

PROVIDER: S-EPMC4198050 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Identification of a gene regulatory network associated with prion replication.

Marbiah Masue M MM Harvey Anna A West Billy T BT Louzolo Anais A Banerjee Priya P Alden Jack J Grigoriadis Anita A Hummerich Holger H Kan Ho-Man HM Cai Ying Y Bloom George S GS Jat Parmjit P Collinge John J Klöhn Peter-Christian PC

The EMBO journal 20140519 14

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, isolate ...[more]

PMID: 24843046

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Identification of a gene regulatory network associated with prion replication.

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Identification of a gene regulatory network associated with prion replication.

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