Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function
Abstract Cardiomyopathy is a co-morbidity of some prion diseases including genetic disease caused by mutations within the PrP gene (PRNP). Although the cellular prion protein (PrP) has been shown to protect against cardiotoxicity caused by oxidative stress, it is unclear if the cardiomyopathy is dir...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-19631-5 |
| _version_ | 1811265135394684928 |
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| author | Aleksandar R. Wood Simote T. Foliaki Bradley R. Groveman Ryan O. Walters Katie Williams Jue Yuan Wen-Quan Zou Cathryn L. Haigh |
| author_facet | Aleksandar R. Wood Simote T. Foliaki Bradley R. Groveman Ryan O. Walters Katie Williams Jue Yuan Wen-Quan Zou Cathryn L. Haigh |
| author_sort | Aleksandar R. Wood |
| collection | DOAJ |
| description | Abstract Cardiomyopathy is a co-morbidity of some prion diseases including genetic disease caused by mutations within the PrP gene (PRNP). Although the cellular prion protein (PrP) has been shown to protect against cardiotoxicity caused by oxidative stress, it is unclear if the cardiomyopathy is directly linked to PrP dysfunction. We differentiated cardiomyocyte cultures from donor human induced pluripotent stem cells and found a direct influence of the PRNP E200K mutation on cellular function. The PRNP E200K cardiomyocytes showed abnormal function evident in the irregularity of the rapid repolarization; a phenotype comparable with the dysfunction reported in Down Syndrome cardiomyocytes. PRNP E200K cardiomyocyte cultures also showed increased mitochondrial superoxide accompanied by increased mitochondrial membrane potential and dysfunction. To confirm that the changes were due to the E200K mutation, CRISPR-Cas9 engineering was used to correct the E200K carrier cells and insert the E200K mutation into control cells. The isotype matched cardiomyocytes showed that the lysine expressing allele does directly influence electrophysiology and mitochondrial function but some differences in severity were apparent between donor lines. Our results demonstrate that cardiomyopathy in hereditary prion disease may be directly linked to PrP dysfunction. |
| first_indexed | 2024-04-12T20:17:22Z |
| format | Article |
| id | doaj.art-882680c5df1d458ba3fb9ad953652c19 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T20:17:22Z |
| publishDate | 2022-09-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-882680c5df1d458ba3fb9ad953652c192022-12-22T03:18:05ZengNature PortfolioScientific Reports2045-23222022-09-0112111510.1038/s41598-022-19631-5Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte functionAleksandar R. Wood0Simote T. Foliaki1Bradley R. Groveman2Ryan O. Walters3Katie Williams4Jue Yuan5Wen-Quan Zou6Cathryn L. Haigh7Laboratory of Persistent Viral Diseases, Division of Intramural Research, Rocky Mountain Laboratories, National Institutes of Health, National Institute of Allergy and Infectious DiseasesLaboratory of Persistent Viral Diseases, Division of Intramural Research, Rocky Mountain Laboratories, National Institutes of Health, National Institute of Allergy and Infectious DiseasesLaboratory of Persistent Viral Diseases, Division of Intramural Research, Rocky Mountain Laboratories, National Institutes of Health, National Institute of Allergy and Infectious DiseasesLaboratory of Persistent Viral Diseases, Division of Intramural Research, Rocky Mountain Laboratories, National Institutes of Health, National Institute of Allergy and Infectious DiseasesLaboratory of Persistent Viral Diseases, Division of Intramural Research, Rocky Mountain Laboratories, National Institutes of Health, National Institute of Allergy and Infectious DiseasesDepartment of Pathology and Neurology, Case Western Reserve University School of MedicineDepartment of Pathology and Neurology, Case Western Reserve University School of MedicineLaboratory of Persistent Viral Diseases, Division of Intramural Research, Rocky Mountain Laboratories, National Institutes of Health, National Institute of Allergy and Infectious DiseasesAbstract Cardiomyopathy is a co-morbidity of some prion diseases including genetic disease caused by mutations within the PrP gene (PRNP). Although the cellular prion protein (PrP) has been shown to protect against cardiotoxicity caused by oxidative stress, it is unclear if the cardiomyopathy is directly linked to PrP dysfunction. We differentiated cardiomyocyte cultures from donor human induced pluripotent stem cells and found a direct influence of the PRNP E200K mutation on cellular function. The PRNP E200K cardiomyocytes showed abnormal function evident in the irregularity of the rapid repolarization; a phenotype comparable with the dysfunction reported in Down Syndrome cardiomyocytes. PRNP E200K cardiomyocyte cultures also showed increased mitochondrial superoxide accompanied by increased mitochondrial membrane potential and dysfunction. To confirm that the changes were due to the E200K mutation, CRISPR-Cas9 engineering was used to correct the E200K carrier cells and insert the E200K mutation into control cells. The isotype matched cardiomyocytes showed that the lysine expressing allele does directly influence electrophysiology and mitochondrial function but some differences in severity were apparent between donor lines. Our results demonstrate that cardiomyopathy in hereditary prion disease may be directly linked to PrP dysfunction.https://doi.org/10.1038/s41598-022-19631-5 |
| spellingShingle | Aleksandar R. Wood Simote T. Foliaki Bradley R. Groveman Ryan O. Walters Katie Williams Jue Yuan Wen-Quan Zou Cathryn L. Haigh Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function Scientific Reports |
| title | Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function |
| title_full | Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function |
| title_fullStr | Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function |
| title_full_unstemmed | Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function |
| title_short | Hereditary E200K mutation within the prion protein gene alters human iPSC derived cardiomyocyte function |
| title_sort | hereditary e200k mutation within the prion protein gene alters human ipsc derived cardiomyocyte function |
| url | https://doi.org/10.1038/s41598-022-19631-5 |
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