Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing
Altered protein conformation can cause incurable neurodegenerative disorders. Mutations in SERPINI1, the gene encoding neuroserpin, can alter protein conformation resulting in cytotoxic aggregation leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare...
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253124003287 |
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| author | Colin T. Konishi Nancy Mulaiese Tanvi Butola Qinkun Zhang Dana Kagan Qiaoyan Yang Mariel Pressler Brooke G. Dirvin Orrin Devinsky Jayeeta Basu Chengzu Long |
| author_facet | Colin T. Konishi Nancy Mulaiese Tanvi Butola Qinkun Zhang Dana Kagan Qiaoyan Yang Mariel Pressler Brooke G. Dirvin Orrin Devinsky Jayeeta Basu Chengzu Long |
| author_sort | Colin T. Konishi |
| collection | DOAJ |
| description | Altered protein conformation can cause incurable neurodegenerative disorders. Mutations in SERPINI1, the gene encoding neuroserpin, can alter protein conformation resulting in cytotoxic aggregation leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy that progresses to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring a patient-specific pathogenic SERPINI1 variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). Here, we utilized a personalized adenine base editor (ABE)-mediated approach to correct the pathogenic variant efficiently and precisely to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted further aggregation. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery, resulting in higher correction efficiency. Our findings provide a targeted strategy that may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimer’s and Huntington’s diseases. |
| format | Article |
| id | doaj-art-5c6dfcdaff0e453baf1051492517fc01 |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-5c6dfcdaff0e453baf1051492517fc012025-01-11T06:41:12ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102441Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editingColin T. Konishi0Nancy Mulaiese1Tanvi Butola2Qinkun Zhang3Dana Kagan4Qiaoyan Yang5Mariel Pressler6Brooke G. Dirvin7Orrin Devinsky8Jayeeta Basu9Chengzu Long10NYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, NY 100016, USA; Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, New York, NY 100016, USANYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, NY 100016, USA; Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, New York, NY 100016, USADepartment of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY 100016, USANYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, NY 100016, USA; Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, New York, NY 100016, USANYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, NY 100016, USA; Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, New York, NY 100016, USANYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, NY 100016, USA; Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, New York, NY 100016, USANYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, NY 100016, USA; Department of Neurology, NYU Grossman School of Medicine, New York, NY 100016, USANYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, NY 100016, USA; Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, New York, NY 100016, USADepartment of Neurology, NYU Grossman School of Medicine, New York, NY 100016, USA; Corresponding author: Orrin Devinsky, Department of Neurology, NYU Grossman School of Medicine, New York, NY 100016, USADepartment of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY 100016, USA; Corresponding author: Jayeeta Basu, Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY 100016, USANYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, NY 100016, USA; Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, New York, NY 100016, USA; Department of Neuroscience and Physiology, NYU Grossman School of Medicine, New York, NY 100016, USA; Department of Neurology, NYU Grossman School of Medicine, New York, NY 100016, USA; Corresponding author: Chengzu Long, NYU Cardiovascular Research Center, NYU Grossman School of Medicine, New York, NY 100016, USAAltered protein conformation can cause incurable neurodegenerative disorders. Mutations in SERPINI1, the gene encoding neuroserpin, can alter protein conformation resulting in cytotoxic aggregation leading to neuronal death. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare autosomal dominant progressive myoclonic epilepsy that progresses to dementia and premature death. We developed HEK293T and induced pluripotent stem cell (iPSC) models of FENIB, harboring a patient-specific pathogenic SERPINI1 variant or stably overexpressing mutant neuroserpin fused to GFP (MUT NS-GFP). Here, we utilized a personalized adenine base editor (ABE)-mediated approach to correct the pathogenic variant efficiently and precisely to restore neuronal dendritic morphology. ABE-treated MUT NS-GFP cells demonstrated reduced inclusion size and number. Using an inducible MUT NS-GFP neuron system, we identified early prevention of toxic protein expression allowed aggregate clearance, while late prevention halted further aggregation. To address several challenges for clinical applications of gene correction, we developed a neuron-specific engineered virus-like particle to optimize neuronal ABE delivery, resulting in higher correction efficiency. Our findings provide a targeted strategy that may treat FENIB and potentially other neurodegenerative diseases due to altered protein conformation such as Alzheimer’s and Huntington’s diseases.http://www.sciencedirect.com/science/article/pii/S2162253124003287MT: RNA/DNA Editingprotein conformational diseaseprotein aggregationiPSC-derived neuronsCRISPR-Cas9adenine base editing |
| spellingShingle | Colin T. Konishi Nancy Mulaiese Tanvi Butola Qinkun Zhang Dana Kagan Qiaoyan Yang Mariel Pressler Brooke G. Dirvin Orrin Devinsky Jayeeta Basu Chengzu Long Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing Molecular Therapy: Nucleic Acids MT: RNA/DNA Editing protein conformational disease protein aggregation iPSC-derived neurons CRISPR-Cas9 adenine base editing |
| title | Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing |
| title_full | Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing |
| title_fullStr | Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing |
| title_full_unstemmed | Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing |
| title_short | Modeling and correction of protein conformational disease in iPSC-derived neurons through personalized base editing |
| title_sort | modeling and correction of protein conformational disease in ipsc derived neurons through personalized base editing |
| topic | MT: RNA/DNA Editing protein conformational disease protein aggregation iPSC-derived neurons CRISPR-Cas9 adenine base editing |
| url | http://www.sciencedirect.com/science/article/pii/S2162253124003287 |
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