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The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics.

ABSTRACT: The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks.

SUBMITTER: Fontaine SN

PROVIDER: S-EPMC4560066 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics.

Fontaine Sarah N SN Martin Mackenzie D MD Akoury Elias E Assimon Victoria A VA Borysov Sergiy S Nordhues Bryce A BA Sabbagh Jonathan J JJ Cockman Matt M Gestwicki Jason E JE Zweckstetter Markus M Dickey Chad A CA

Human molecular genetics 20150416 14

The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In parti ...[more]

PMID: 25882706

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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

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics.

Publications

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics.

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