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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

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 pri...

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Autores principales: Foliaki, Simote T., Groveman, Bradley R., Yuan, Jue, Walters, Ryan, Zhang, Shulin, Tesar, Paul, Zou, Wenquan, Haigh, Cathryn L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350378/
https://www.ncbi.nlm.nih.gov/pubmed/32570796
http://dx.doi.org/10.3390/pathogens9060482
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author Foliaki, Simote T.
Groveman, Bradley R.
Yuan, Jue
Walters, Ryan
Zhang, Shulin
Tesar, Paul
Zou, Wenquan
Haigh, Cathryn L.
author_facet Foliaki, Simote T.
Groveman, Bradley R.
Yuan, Jue
Walters, Ryan
Zhang, Shulin
Tesar, Paul
Zou, Wenquan
Haigh, Cathryn L.
author_sort Foliaki, Simote T.
collection PubMed
description 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.
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spelling pubmed-73503782020-07-15 Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease Foliaki, Simote T. Groveman, Bradley R. Yuan, Jue Walters, Ryan Zhang, Shulin Tesar, Paul Zou, Wenquan Haigh, Cathryn L. Pathogens Article 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. MDPI 2020-06-18 /pmc/articles/PMC7350378/ /pubmed/32570796 http://dx.doi.org/10.3390/pathogens9060482 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Foliaki, Simote T.
Groveman, Bradley R.
Yuan, Jue
Walters, Ryan
Zhang, Shulin
Tesar, Paul
Zou, Wenquan
Haigh, Cathryn L.
Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease
title Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease
title_full Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease
title_fullStr Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease
title_full_unstemmed Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease
title_short Pathogenic Prion Protein Isoforms Are Not Present in Cerebral Organoids Generated from Asymptomatic Donors Carrying the E200K Mutation Associated with Familial Prion Disease
title_sort pathogenic prion protein isoforms are not present in cerebral organoids generated from asymptomatic donors carrying the e200k mutation associated with familial prion disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350378/
https://www.ncbi.nlm.nih.gov/pubmed/32570796
http://dx.doi.org/10.3390/pathogens9060482
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