Abstract

ABSTRACT 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.

Full Text

Published Version

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.