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MRC Prion Unit
From fundamental research to prevention and cure

Cellular mechanisms of prion propagation

Prions, the infectious agents that cause the lethal brain disease Creutzfeldt-Jakob disease (CJD) in humans infect a range of different cells in the body. In contrast to other infectious diseases, like viral or bacterial diseases, prions are not recognised as rogue proteins by the immune system and the hosts remain symptom-free for a long period of time. During this phase prions rapidly multiply in lymphoid organs, like the spleen, lymph nodes or tonsils and finally reach the brain where they cause a fatal and progressive loss of neurons.

We seek to better understand the cellular basis of prion susceptibility and how prions spread in the body. We use two principal approaches: firstly, to better understand why the majority of nerve cell lines do not allow prions to propagate, we identify genes that are associated with susceptibility to prion propagation (Marbiah et al. 2014); and secondly, we examine prion infection of blood cell populations during the early stages after prion infection to better characterise the role of immune cells in prion disease (Castro-Seoane et al. 2012).

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Figure 1. To investigate genes that contribute to prion propagation we establish cell models and diagnostic assays. As shown in panel A, the prion protein (PrP) can be visualised in healthy (control) and prion-infected cells with antisera against PrP. Whereas PrP decorates the membranes in control cells, aggregates of misfolded PrP are apparent in the periphery of infected cells. In the Scrapie Cell Assay (panel B) we can quantify the degree of prion infection. Each of the black spots depicted on the filters in panel B represents a prion-infected cell.    


Figure 2. The use of primary neuronal cells is critical in our studies to investigate the response of cells to aggregates of rogue proteins. As shown in the image above, aggregated disease-associated PrP is decorating the processes of neuronal cells. Panel a on the right is a magnification of the left image.

We continue to advance the development of cell-based bioassays of prion “strains”, which are of wide importance to prion research and other neurodegenerative diseases. We seek to apply our established expertise to develop analogous tools to assay ’prion-like’ mechanisms in Alzheimer’s disease as part of wider developments within the Unit to explore the importance and pathogenetic relevance of these mechanisms in other neurodegenerative diseases. Advances in our understanding of genetic pathways of prion neurodegeneration are likely to also be of wider relevance in neurodegenerative disease. Our continuing endeavour to implement novel technologies in molecular and synthetic biology in the Unit underpins our aim to advance our understanding of the neurodegenerative processes and how they may be halted.


Exosome release from infected dendritic cells: A clue for a fast spread of prions in the periphery
Kloehn PC, Castro-Seoane R, Collinge J.  J Infect 2013; 67: 359-368.

Peer reviewed articles:

Identification of a gene regulatory network associated with prion replication
Marbiah M, 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. EMBO J 2014

In-vitro screen of prion disease susceptibility genes using the scrapie cell assay
Brown CA, Schmidt C, Poulter M, Hummerich H, Klöhn PC, Jat P, Mead S, Collinge J, Lloyd SE.
Hum Mol Genet 2014


Plasmacytoid dendritic cells sequester high prion titres at early stages of prion infection
Castro-Seoane R, Hummerich H, Sweeting T, Tattum HM, Linehan JM, Fernandez de Marco M, Brandner S, Collinge J, Klöhn PC.  PLoS Pathog 2012; 8: e1002538..

Prion protein antibodies do not trigger mouse hippocampal neuron apoptosis.
Klöhn PC, Farmer M, Linehan JM, O'Malley C, Fernandez de Marco M, Taylor W, Farrow M, Khalili-Shirazi A, Brandner S, Collinge J. Science 2012; 335: 52.