Seminar by Dr. Peter Klohen - "Identification of a regulatory gene network associated with self-replicating infectious prions in neuronal cells"

Date

2016年5月9日 (月) 10:00 11:00

Location

Seminar Room C209, Center Bldg.

Description

 

 

Peter Kloehn, Ph.D.

MRC Prion Unit and Department of Neurodegenerative Disease

UCL Institute of Neurology

Queen Square, London

 

Title: Identification of a regulatory gene network associated with self-replicating infectious prions in neuronal cells

Prions are hitherto unique infectious pathogens that cause a group of invariably fatal neurological disorders, Transmissible Spongiform Encephalopathies (TSE). Prions consist of aggregated abnormal conformers of cellular prion protein (PrP) and propagate by recruiting PrP into seeds of misfolded PrP although the critical interacting proteins are unknown. We derived a lineage of cell lines with markedly differing susceptibilities, unexplained by their PrP expression levels, to identify such factors. Transcriptome analysis of prion-resistant revertants, isolated from highly susceptible cells, revealed a gene expression signature that was associated with susceptibility and modulated by cellular differentiation. Several of these genes encode proteins with a role in extracellular matrix (ECM) remodelling.

To better understand how this gene signature modulates prion propagation, we investigated loss-of-function phenotypes. Transcriptional silencing of these genes significantly increased the susceptibility of revertants to propagate prions. In addition, silencing of Papss2 led to undersulfated heparan sulfate and increased PrP deposition at the ECM. Moreover, inhibition of fibronectin 1 binding to integrin α8 by RGD peptide inhibited metalloproteinases (MMP)-2/9.

In summary, we have identified a gene regulatory network associated with prion propagation at the ECM and governed by the cellular differentiation state.

 

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