Gene expression differences between prion-resistant and prion-susceptible cells

Prions consist of aggregates of abnormal conformers of cellular prion protein (PrPC). They propagate by recruiting host-encoded PrPC 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 PrPC expression differences, to identify such factors. We examined the transcriptomes of prion-resistant revertants, isolated from highly susceptible cells, and identified a gene expression signature associated with susceptibility. Several of these genes encode proteins with a role in extracellular matrix (ECM) remodelling, a compartment in which disease-related PrP deposits. Loss-of-function of nine of these genes significantly increased susceptibility. Remarkably, inhibition of fibronectin 1 binding to integrin 8 by RGD peptide inhibited metalloproteinases (MMP)-2/9 whilst increasing prion propagation rates. This indicates that prion replication may be controlled by MMPs at the ECM in an integrin-dependent manner.

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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