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Abstract
Prions are infectious agents that cause neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD). The absence of a human cell culture model that replicates human prions has hampered prion disease research for decades. In this paper, we show that astrocytes derived from human induced pluripotent stem cells (iPSCs) support the replication of prions from brain samples of CJD patients. For experimental exposure of astrocytes to variant CJD (vCJD), the kinetics of prion replication occur in a prion protein codon 129 genotype–dependent manner, reflecting the genotype-dependent susceptibility to clinical vCJD found in patients. Furthermore, iPSC-derived astrocytes can replicate prions associated with the major sporadic CJD strains found in human patients. Lastly, we demonstrate the subpassage of prions from infected to naive astrocyte cultures, indicating the generation of prion infectivity in vitro. Our study addresses a long-standing gap in the repertoire of human prion disease research, providing a new in vitro system for accelerated mechanistic studies and drug discovery.
Original language | English |
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Pages (from-to) | 3481-3495 |
Number of pages | 15 |
Journal | Journal of Experimental Medicine |
Volume | 214 |
Issue number | 12 |
DOIs | |
Publication status | Published - 15 Nov 2017 |
Keywords
- Journal Article
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Profiles
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Siddharthan Chandran
- Deanery of Clinical Sciences - MacDonald Chair of Neurology
- Centre for Clinical Brain Sciences
- Euan MacDonald Centre for Motor Neuron Disease Research
- Centre for Regenerative Medicine
- Anne Rowling Regenerative Neurology Clinic
- Edinburgh Neuroscience
- Edinburgh Imaging
Person: Academic: Research Active