Prion diseases are fatal neurodegenerative conditions associated with misfolding of the normal form of the prion protein. The mechanism of neuronal dysfunction and death are not well understood and effective therapies are lacking. Some human prion diseases are acquired, most forms are transmissible, and all forms are thought to proceed by the seeded spread of prion protein misfolding in the brain. Factors known to affect susceptibility to prion infection include the strain of prion agent and host prion protein genotype. Prion disease research benefits from excellent animal models and more recently the molecular pathology has been modelled using cell-free assays, but there is a manifest gap in human prion disease research in the area of cell biology. At present there are no normal human cells that have been shown to be susceptible to infection with human prions in vitro. This places constraints on studies of human prion detection, replication, cellular susceptibility, neurotoxic mechanism and candidate therapeutic agents.
We propose that neurones and astrocytes derived from human stem cells offer a promising route to a cell culture model of human prion infection and replication. Our preliminary data shows that astrocytes derived from human induced pluripotent stem cells can be infected with variant Creutzfeldt-Jakob disease prions from human brain tissue samples. Further, that susceptibility is genotype dependent. We wish to capitalise on this observation by extending these studies to induced pluripotent stem cell-derived neurones, examine effects of prion agent strain and host cell genotype on susceptibility and determine what the effects of prion infection are on neuronal and astrocytic function. These studies will demonstrate the potential for human stem cell-derived neurones and astrocytes to replace animal models in numerous aspects of human prion disease research.
Krejciova Z et al. (2017). Human stem cell–derived astrocytes replicate human prions in a PRNP genotype–dependent manner. Journal of Experimental Medicine 214(12):3481. doi: 10.1084/jem.20161547