Antibody-mediated degradation of 4R-tau restores mitochondrial membrane polarization in human induced pluripotent stem cell-derived neurons with the MAPT 10+16 mutation
Summary
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.
| Authors | Starkie DO, Arber C, Baker T, Lightwood DJ, Wray S |
|---|---|
| Journal | mAbs |
| Publication Date | 2024 Jan-Dec;16(1):2436102 |
| PubMed | 39665388 |
| PubMed Central | PMC11790244 |
| DOI | 10.1080/19420862.2024.2436102 |