Human stem cell-derived astrocytes replicate human prions in a PRNP genotype-dependent manner

Zuzana Krejciova, James Alibhai, Chen Zhao, Robert Krencik, Nina M. Rzechorzek, Erik M. Ullian, Jean Manson, James W. Ironside, Mark W. Head, Siddharthan Chandran

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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 languageEnglish (US)
Pages (from-to)3481-3495
Number of pages15
JournalThe Journal of experimental medicine
Volume214
Issue number12
DOIs
StatePublished - Dec 4 2017

Keywords

  • Journal Article

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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