Parmjit Jat
Parmjit Jat
Cell Biology: Cellular Functions of the
Prion Protein

Parmjit studied Biochemistry at the University of Bath (1974-1978) and undertook his PhD In Molecular Biology at the Imperial Cancer Research Fund (now CRUK) and Imperial College London from 1978-1982.

This was followed by Postdoctoral research (1983-1987) at the Massachusetts Institute of Technology Centre for Cancer Research (Cambridge, USA) in the laboratory of Dr Philip Sharp working on Cell Immortalisation.

From 1987 to 2003 he was a Group Leader and Head of Transformation Studies at the UCL Branch of the Ludwig Institute for Cancer Research working on Cellular Senescence and Cancer.

Since 2003, he has been a Professor of Molecular Cellular Biology within the Department of Neurodegenerative Disease at the UCL Institute of Neurology and joined the MRC Prion Unit in 2013 to lead the Cell Biology Programme.

Prion diseases such as Creutzfeldt-Jakob diseases (CJD) in humans and bovine spongiform encephalopathy in cows are severe, devastating intractable diseases.  CJD is a rapidly progressive, ultimately fatal degenerative brain disorder that leads to dementia as well as other neurological symptoms.  Prion diseases are caused by infectious agents found in many animal species including sheep, cows, and deer, as well as humans.  The infectious agent is composed of aggregates of a misfolded form (PrPSc) of the cellular prion protein (PrPC).  This is unique as normally a pathogen carries genetic material in the form of DNA or RNA for replicating infectivity, whereas in prion disease, PrPSc, a protein, acts as a template to convert PrPC to the disease state.

PrPC is a cell-surface protein, expressed in most cell types throughout the body. It has a variety of activities and functions within cells including signalling for cell survival and metabolism, rather than a sole unitary function. One very important function of PrPC is that it is absolutely required for prion propagation: mice devoid of PrPC are resistant to prion infection. 

Cell lines are an invaluable tool to study complex cell processes and diseases including aspects of prion biology.  However, the use of cell culture systems to study prion propagation is 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, despite worldwide efforts. 

Currently human prions are propagated in mice that lack mouse PrPC but have been engineered to express human PrPC. The development of PK1 cells by colleagues within the MRC Prion Unit, by extensive serial sub-cloning of mouse neuroblastoma N2a cells, that can efficiently propagate Rocky Mountain Laboratory mouse prions has permitted the development of a cell culture based bioassay for mouse prions and revolutionised their study.

Our aim is to develop cells that can propagate human prions, both sporadic (s) and variant (v) CJD prions. We will use a “silencing reconstitution strategy” that recapitulates the approach used to make mouse models of human and other prion diseases. This will enable us to develop robust, highly sensitive, automated cell culture assays for measuring human prion infectivity in vitro.

Recent advances within the Unit and elsewhere suggest that prions themselves are not directly toxic, but rather their propagation involves production of a toxic species uncoupled from infectious prions. Clinical disease is only observed after prion infectivity peaks followed by a time lag which is inversely proportional to the level of PrPC expression. We aim is to identify the toxic species in prion disease by developing an in vitro assay for prion-induced neurotoxic activity to enable its detection throughout the course of prion infection and to facilitate the fractionation and isolation of the toxic species.