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Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease

Authors :
Simote T. Foliaki
Bradley R. Groveman
Jue Yuan
Ryan Walters
Shulin Zhang
Paul Tesar
Wenquan Zou
Cathryn L. Haigh
Source :
Pathogens, Vol 9, Iss 6, p 482 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

Cerebral organoids (COs) are a self-organizing three-dimensional brain tissue mimicking the human cerebral cortex. COs are a promising new system for modelling pathological features of neurological disorders, including prion diseases. COs expressing normal prion protein (PrPC) are susceptible to prion infection when exposed to the disease isoforms of PrP (PrPD). This causes the COs to develop aspects of prion disease pathology considered hallmarks of disease, including the production of detergent-insoluble, protease-resistant misfolded PrPD species capable of seeding the production of more misfolded species. To determine whether COs can model aspects of familial prion diseases, we produced COs from donor fibroblasts carrying the E200K mutation, the most common cause of human familial prion disease. The mature E200K COs were assessed for the hallmarks of prion disease. We found that up to 12 months post-differentiation, E200K COs harbored no PrPD as confirmed by the absence of detergent-insoluble, protease-resistant, and seeding-active PrP species. Our results suggest that the presence of the E200K mutation within the prion gene is insufficient to cause disease in neuronal tissue. Therefore, other factors, such as further genetic modifiers or aging processes, may influence the onset of misfolding.

Details

Language :
English
ISSN :
20760817
Volume :
9
Issue :
6
Database :
Directory of Open Access Journals
Journal :
Pathogens
Publication Type :
Academic Journal
Accession number :
edsdoj.15c1c79f7938430692217cfa351abca5
Document Type :
article
Full Text :
https://doi.org/10.3390/pathogens9060482