Abstract / Description of output
The fundamental mechanisms involved in chronic neurodegenerative diseases can be investigated using
human tissue based approaches, animal models and in vitro cellular and cell-free models. In practice, a
combination of these approaches is usually required to study human disease mechanisms. In human prion
disease research, a significant impeding factor has been the absence of a human cell culture model in which
human prions replicate efficiently and reproducibly.
To address this issue, we have tested whether human induced pluripotent stem cells (iPSC) differentiated
into mature astrocytes or neurons support prion replication. The iPSCs were derived from donors with no
family history of neurological disorders and with no known disease-associated mutations. All cell lines were
of known PRNP codon 129 genotype, an important polymorphism site which can play a role in defining
susceptibility and/or clinical manifestations of several human prion diseases, including the 129MM genotype
associated with variant Creutzfeldt-Jakob disease (vCJD).
Upon experimental infection, we found that PRNP codon 129MM astrocytes supported vCJD prion replication
efficiently, whereas astrocytes of the PRNP codon 129MV genotype were comparably resilient, only showing
evidence of prion replication substantially later than 129MM astrocytes. This corresponds to human
epidemiological data and therefore accurately models human prion susceptibility. Furthermore, we have
expanded our findings to show cell susceptibility to prion replication after experimental infection with a range
of different human prion strains and similarly highlight the importance of genotype-matching between strain
and host. Finally, we demonstrate that prion replication in astrocytes correlates with infectivity by sub-
passage of astrocyte-infected inoculate.
Our study therefore addresses a long-standing gap in the repertoire of human prion disease research, and
provides a model that can be used to investigate human prion disease mechanisms
human tissue based approaches, animal models and in vitro cellular and cell-free models. In practice, a
combination of these approaches is usually required to study human disease mechanisms. In human prion
disease research, a significant impeding factor has been the absence of a human cell culture model in which
human prions replicate efficiently and reproducibly.
To address this issue, we have tested whether human induced pluripotent stem cells (iPSC) differentiated
into mature astrocytes or neurons support prion replication. The iPSCs were derived from donors with no
family history of neurological disorders and with no known disease-associated mutations. All cell lines were
of known PRNP codon 129 genotype, an important polymorphism site which can play a role in defining
susceptibility and/or clinical manifestations of several human prion diseases, including the 129MM genotype
associated with variant Creutzfeldt-Jakob disease (vCJD).
Upon experimental infection, we found that PRNP codon 129MM astrocytes supported vCJD prion replication
efficiently, whereas astrocytes of the PRNP codon 129MV genotype were comparably resilient, only showing
evidence of prion replication substantially later than 129MM astrocytes. This corresponds to human
epidemiological data and therefore accurately models human prion susceptibility. Furthermore, we have
expanded our findings to show cell susceptibility to prion replication after experimental infection with a range
of different human prion strains and similarly highlight the importance of genotype-matching between strain
and host. Finally, we demonstrate that prion replication in astrocytes correlates with infectivity by sub-
passage of astrocyte-infected inoculate.
Our study therefore addresses a long-standing gap in the repertoire of human prion disease research, and
provides a model that can be used to investigate human prion disease mechanisms
| Original language | English |
|---|---|
| Pages (from-to) | E184-E184 |
| Number of pages | 1 |
| Journal | Glia |
| Volume | 65 |
| Issue number | S1 |
| DOIs | |
| Publication status | Published - Jun 2017 |
| Event | 13th European Meeting on Glial Cells in Health and Disease - Edinburgh Duration: 8 Jul 2017 → 11 Jul 2017 |