Activated cofilin exacerbates tau pathology by impairing tau-mediated microtubule dynamics

• Published in: Communications biology Vol. 2; no. 1; p. 112
• Main Authors: Woo, Jung-A. A., Liu, Tian, Fang, Cenxiao C., Cazzaro, Sara, Kee, Teresa, LePochat, Patrick, Yrigoin, Ksenia, Penn, Courtney, Zhao, Xingyu, Wang, Xinming, Liggett, Stephen B., Kang, David E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-03-2019; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/51; 14; 14/1; 14/34; 14/35; 631/378/1689/1283; 631/80/304; 64/11; 64/60; 9/30; Actin; Actin Depolymerizing Factors - genetics; Actin Depolymerizing Factors - metabolism; Alzheimer's disease; Animals; Biology; Biomedical and Life Sciences; Caenorhabditis elegans; Cofilin; Dementia disorders; Disease Models, Animal; Etiology; Life Sciences; Mice; Mice, Knockout; Microtubule-associated proteins; Microtubules - metabolism; Neurodegenerative diseases; Neurons - metabolism; Neurotoxicity; Protein Binding; Tau protein; tau Proteins - genetics; tau Proteins - metabolism; Tauopathies - etiology; Tauopathies - metabolism; Transcriptional Activation; Tubulin; Tubulin - metabolism; β-Amyloid
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-019-0359-9

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. While the accumulation of Aβ is pivotal to the etiology of AD, both the microtubule-associated protein tau (MAPT) and the F-actin severing protein cofilin are necessary for the deleterious effects of Aβ. However, the molecular link between tau and cofilin remains unclear. In this study, we found that cofilin competes with tau for direct microtubule binding in vitro, in cells, and in vivo, which inhibits tau-induced microtubule assembly. Genetic reduction of
cofilin
mitigates tauopathy and synaptic defects in Tau-P301S mice and movement deficits in tau transgenic
C. elegans
. The pathogenic effects of cofilin are selectively mediated by activated cofilin, as active but not inactive cofilin selectively interacts with tubulin, destabilizes microtubules, and promotes tauopathy. These results therefore indicate that activated cofilin plays an essential intermediary role in neurotoxic signaling that promotes tauopathy.
Jung-A A. Woo et al. show that activated cofilin competes with Tau for microtubule biding in primary neuronal cultures and a
C.elegans
model. This direct binding decreases microtubule stability and promotes tauopathy, suggesting an important role for cofilin in neurotoxic signaling.