Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation
Microtubule-associated protein tau is inextricably linked to a group of clinically diverse neurodegenerative diseases termed tauopathies. The ratio balance of the major tau splicing isoform groups (3 R- and 4 R-tau) is critical in maintaining healthy neurons. An imbalance causing excess 4 R tau is a...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2436102 |
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| author | Dale O. Starkie Charles Arber Terry Baker Daniel J. Lightwood Selina Wray |
| author_facet | Dale O. Starkie Charles Arber Terry Baker Daniel J. Lightwood Selina Wray |
| author_sort | Dale O. Starkie |
| collection | DOAJ |
| description | Microtubule-associated protein tau is inextricably linked to a group of clinically diverse neurodegenerative diseases termed tauopathies. The ratio balance of the major tau splicing isoform groups (3 R- and 4 R-tau) is critical in maintaining healthy neurons. An imbalance causing excess 4 R tau is associated with diseases such as progressive supranuclear palsy and frontotemporal dementia. The mechanisms by which increased 4 R results in neuronal dysfunction and neurodegeneration are not fully understood, and progress has been limited partly by a lack of suitable tools to investigate tau isoform imbalance. This work generated novel 3 R- and 4 R-specific antibody tools and 4 R-tau degrading intracellular antibody fragment “degrabodies”. These were used to probe the molecular mechanisms of excess 4 R-tau in disease-mutant induced pluripotent stem cell-derived neurons. For the first time, we demonstrate a causative link between excess 4 R-tau and mitochondrial membrane hyperpolarization with wide-ranging potential for elucidating novel therapeutic approaches to treat neurodegenerative disease. |
| format | Article |
| id | doaj-art-9297d8ec05824b7c802c145729c35762 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-9297d8ec05824b7c802c145729c357622025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2436102Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutationDale O. Starkie0Charles Arber1Terry Baker2Daniel J. Lightwood3Selina Wray4Antibody Discovery and Optimization, UCB Pharma, Slough, Berkshire, UKDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United KingdomAntibody Discovery and Optimization, UCB Pharma, Slough, Berkshire, UKAntibody Discovery and Optimization, UCB Pharma, Slough, Berkshire, UKDepartment of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United KingdomMicrotubule-associated protein tau is inextricably linked to a group of clinically diverse neurodegenerative diseases termed tauopathies. The ratio balance of the major tau splicing isoform groups (3 R- and 4 R-tau) is critical in maintaining healthy neurons. An imbalance causing excess 4 R tau is associated with diseases such as progressive supranuclear palsy and frontotemporal dementia. The mechanisms by which increased 4 R results in neuronal dysfunction and neurodegeneration are not fully understood, and progress has been limited partly by a lack of suitable tools to investigate tau isoform imbalance. This work generated novel 3 R- and 4 R-specific antibody tools and 4 R-tau degrading intracellular antibody fragment “degrabodies”. These were used to probe the molecular mechanisms of excess 4 R-tau in disease-mutant induced pluripotent stem cell-derived neurons. For the first time, we demonstrate a causative link between excess 4 R-tau and mitochondrial membrane hyperpolarization with wide-ranging potential for elucidating novel therapeutic approaches to treat neurodegenerative disease.https://www.tandfonline.com/doi/10.1080/19420862.2024.2436102Antibody Discoverydegrabodiesdegrading antibody fragmentsintracellular antibody technologiesiPSC-derrived neuronstargeted protein degradation |
| spellingShingle | Dale O. Starkie Charles Arber Terry Baker Daniel J. Lightwood Selina Wray Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation mAbs Antibody Discovery degrabodies degrading antibody fragments intracellular antibody technologies iPSC-derrived neurons targeted protein degradation |
| title | Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation |
| title_full | Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation |
| title_fullStr | Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation |
| title_full_unstemmed | Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation |
| title_short | Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation |
| title_sort | antibody mediated degradation of 4r tau restores mitochondrial membrane polarization in human induced pluripotent stem cell derived neurons with the mapt 10 16 mutation |
| topic | Antibody Discovery degrabodies degrading antibody fragments intracellular antibody technologies iPSC-derrived neurons targeted protein degradation |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2436102 |
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