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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

1
Laboratory of Persistent Viral Diseases, National Institute of Allergy and Infectious Diseases, Division of Intramural Research, Rocky Mountain Laboratories, National Institutes of Health, 903 South 4th Street, Hamilton, MT 59840, USA
2
Departments of Pathology and Neurology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
3
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
*
Author to whom correspondence should be addressed.
Current address: Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USA.
Pathogens 2020, 9(6), 482; https://doi.org/10.3390/pathogens9060482
Received: 25 May 2020 / Revised: 12 June 2020 / Accepted: 17 June 2020 / Published: 18 June 2020
(This article belongs to the Section Human Pathogens)
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. View Full-Text
Keywords: prion; CJD; E200K; cerebral organoid; iPSC prion; CJD; E200K; cerebral organoid; iPSC
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Foliaki, S.T.; Groveman, B.R.; Yuan, J.; Walters, R.; Zhang, S.; Tesar, P.; Zou, W.; Haigh, C.L. Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease. Pathogens 2020, 9, 482.

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