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MRC Prion Unit and Institute of Prion disease

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Parmjit Jat

Cell biology: Cellular functions of the prion protein

Parmjit Jat

p.jat@prion.ucl.ac.uk

Tel: 020 7679 5137
Courtauld Building, Room 101B

UCL Profile • PubMed

 

List of Funders
Medical Research Council
Department of Health: Policy Research Programme

Research Themes
Prion biology
Prion propagation
Prion induced toxicity
Cell models,
Cancer biology
Regeneration
Cell immortalisation

Technology used                                                                                                            
Cell culture
Scrapie cell assay
Confocal microscopy,
High content confocal microscopy
Incucyte live cell imaging
Retroviral/lentiviral mediated RNA silencing
Retroviral/ lentiviral mediated ectopic expression
Bioinformatics

People
Iryna Benilova (Investigator Scientist)
Parineeta Arora (Investigator Scientist)
Madeleine Reilly (PhD student)
Akin Nihat (Clinical PhD student)
Azy Khalili

List of collaborators
James Phillips (UCL School of Pharmacy, UK)
Rickie Patani (UCL Queen Square Institute of Neurology, UK)
David Choi (UCL Queen Square Institute of Neurology, UK)
Sunil R Lakhani (The University of Queensland & Pathology, Queensland, Australia)
Ernesto Yague (Imperial College London, UK)
Ivan Wall (University of Aston, UK)
Jacques van Snick (Ludwig Cancer Research Ltd Brussels Branch, Belgium)
Bernhard Ryffel (CNRS-University of Orleans, France)
Lily Wu (University of California, USA)
Judith Blaine (University of Colorado Denver, USA)

Research Synopsis

Cell lines are an invaluable tool for studying complex processes and diseases. Cell culture systems to study prion biology are limited to a few cell lines susceptible to either mouse-adapted or sheep prion strains, with none yet described able to stably propagate human prions. 

We aim to develop cells that can propagate human variant and sporadic Creutzfeldt-Jakob disease prions by using a “silencing-reconstitution strategy” that recapitulates the approach used to make mouse models of human prion disease.  This will enable us to develop a robust highly sensitive, automated cell culture assay for human prion infectivity.

Recent work has suggested prions themselves are not directly toxic but lead to the production of a toxic species.  To identify the toxic species, we have developed a multi-parametric high content imaging assay of neurotoxic phenotypes.  We will use this assay to examine toxicity through the course of a prion infection, isolate the toxic species and investigate the mechanism of action.

Parmjit Jat Fig 1

OPERA confocal micrograph of primary neurons grown in 96-well plate treated with RML brain homogenate for 72h or left untreated.
Three phenotypic parameters were measured from multiple images per condition using cell model-optimized scripts.

Selected Publications

A systematic investigation of production of synthetic prions from recombinant prion protein
Schmidt C, Fizet J, Properzi F, Batchelor M, Sandberg MK, Edgeworth JA, Afran L, Ho S, Badhan A, Klier S, Linehan JM, Brandner S, Hosszu LL, Tattum MH, Jat P, Clarke AR, Klöhn PC, Wadsworth JD, Jackson GS, Collinge J. Open Biol. 2015 Dec;5(12):150165. doi: 10.1098/rsob.150165. PMID:  26631378

Identification of clinical target areas in the brainstem of prion-infected mice.
Mirabile I, Jat PS, Brandner S, Collinge J. Neuropathol Appl Neurobiol. 2015 Aug;41(5):613-30. doi: 10.1111/nan.12189. Epub 2015 Apr 23. PMID: 25311251

Identification of a gene regulatory network associated with prion replication.
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. EMBO J. 2014 Jul 17;33(14):1527-47. doi: 10.15252/embj.201387150. Epub 2014 May 19. PMID: 24843046

Activation of nuclear factor-kappa B signalling promotes cellular senescence.
Rovillain E, Mansfield L, Caetano C, Alvarez-Fernandez M, Caballero OL, Medema RH, Hummerich H, Jat PS. Oncogene. 2011 May 19;30(20):2356-66. doi: 10.1038/onc.2010.611. Epub 2011 Jan 17. PMID:  21242976

Conditional immortalization of freshly isolated human mammary fibroblasts and endothelial cells.
O'Hare MJ, Bond J, Clarke C, Takeuchi Y, Atherton AJ, Berry C, Moody J, Silver ARJ, Davies DC, Alsop AE, Neville AM, Jat PS. Proc. Natl. Acad. Sci. USA 2001; 98: 646-651.

Recovery of spatial learning by grafts of a conditionally-immortalised hippocampal neuroepithelial cell line into the ischaemia-lesioned hippocampus
Sinden JD, Rashid-Doubell F, Kershaw TR, Nelson A, Chadwick A, Jat PS, Noble MD, Hodges H, Gray JA. .  Neuroscience 1997; 81: 599-608. 

Direct derivation of conditionally immortal cell lines from an H-2KB-tsA58 transgenic mouse
Jat PS, Noble MD, Ataliotis P, Tanaka Y, Yannoutsos N, Larsen L, Kioussis D.   Proc. Natl. Acad. Sci USA 1991; 88: 5096-5100.