Dataset Information

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

ABSTRACT: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. While the accumulation of A? 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 A?. 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.

SUBMITTER: Woo JA

PROVIDER: S-EPMC6430779 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Woo Jung-A A JA Liu Tian T Fang Cenxiao C CC Cazzaro Sara S Kee Teresa T LePochat Patrick P Yrigoin Ksenia K Penn Courtney C Zhao Xingyu X Wang Xinming X Liggett Stephen B SB Kang David E DE

Communications biology 20190322

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, w ...[more]

PMID: 30911686

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Project description:Microtubule-associated protein (MAP) tau is a cross-linking molecule that provides structural stability to axonal microtubules (MT). It is considered a potential biomarker for Alzheimer's disease (AD), dementia, and other neurological disorders. It is also a signature protein for Traumatic Brain Injury (TBI) assessment. In the case of TBI, extreme dynamic mechanical energies can be felt by the axonal cytoskeletal members. As such, fundamental understandings of the responses of single tau protein, polymerized tau protein, and tau-microtubule interfaces under high-rate mechanical forces are important. This study attempts to determine the high-strain rate mechanical behavior of single tau, dimerized tau, and tau-MT interface using molecular dynamics (MD) simulation. The results show that a single tau protein is a highly stretchable soft polymer. During deformation, first, it significantly unfolds against van der Waals and electrostatic bonds. Then it stretches against strong covalent bonds. We found that tau acts as a viscoelastic material, and its stiffness increases with the strain rate. The unfolding stiffness can be ~50-500 MPa, while pure stretching stiffness can be >2 GPa. The dimerized tau model exhibits similar behavior under similar strain rates, and tau sliding from another tau is not observed until it is stretched to >7 times of original length, depending on the strain rate. The tau-MT interface simulations show that very high strain and strain rates are required to separate tau from MT suggesting Tau-MT bonding is stronger than MT subunit bonding between themselves. The dimerized tau-MT interface simulations suggest that tau-tau bonding is stronger than tau-MT bonding. In summary, this study focuses on the structural response of individual cytoskeletal components, namely microtubule (MT) and tau protein. Furthermore, we consider not only the individual response of a component, but also their interaction with each other (such as tau with tau or tau with MT). This study will eventually pave the way to build a bottom-up multiscale brain model and analyze TBI more comprehensively.

Dataset Information

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

Publications

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

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