Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly.

Goode, Bruce L.; Denis, Paul; Panda, Dulal; Radeke, Monte J.; Miller, Herbert C.; Wilson, Leslie; Feinstein, Stuart C.

doi:10.1091/mbc.8.2.353

Cited by 259 publications

(225 citation statements)

References 84 publications

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“…However, Hsc70 required functional tau to promote MT dynamics, suggesting the novel concept that tau binds to Hsc70 as a client, but functions with Hsc70 to facilitate MT assembly, an idea supported by the fact that tau binds the substrate-binding domain of Hsc70. This newly described function may help to explain why tau is so sensitive to chaperone modulation despite its intrinsically disordered structure: Tau is used by the chaperone network to regulate MT stability (35,36,38,39). But interestingly, if tau has a disease-causing mutation, it can still interact with Hsc70, yet prevents MT assembly, adding Hsc70 as a new player to this pathogenic mechanism for tauopathy-causing mutations.…”

Section: Discussionmentioning

confidence: 99%

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

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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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.

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Section: Discussionmentioning

confidence: 99%

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

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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“…Tau protein was expressed and purified by a modification of the procedures described in Goode et al (1997). Briefly, tau expression was induced in Rosetta (DE3) pLacI cells (Novagen, Madison, WI) by adding isopropyl-␤-d-thiogalactoside to a final concentration of 1 mM.…”

Section: Tau Protein Purificationmentioning

confidence: 99%

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Bunker

Wilson

Jordan

et al. 2004

MBoC

132

126

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The neural microtubule-associated protein tau binds to and stabilizes microtubules. Because of alternative mRNA splicing, tau is expressed with either 3 or 4 C-terminal repeats. Two observations indicate that differences between these tau isoforms are functionally important. First, the pattern of tau isoform expression is tightly regulated during development. Second, mutation-induced changes in tau RNA splicing cause neuronal cell death and dementia simply by altering the isoform expression ratio. To investigate whether 3-and 4-repeat tau differentially regulate microtubule behavior in cells, we microinjected physiological levels of these two isoforms into EGFP-tubulin-expressing cultured MCF7 cells and measured the effects on the dynamic instability behavior of individual microtubules by time-lapse microscopy. Both isoforms suppressed microtubule dynamics, though to different extents. Specifically, 4-repeat tau reduced the rate and extent of both growing and shortening events. In contrast, 3-repeat tau stabilized most dynamic parameters about threefold less potently than 4-repeat tau and had only a minimal ability to suppress shortening events. These differences provide a mechanistic rationale for the developmental shift in tau isoform expression and are consistent with a loss-of-function model in which abnormal tau isoform expression results in the inability to properly regulate microtubule dynamics, leading to neuronal cell death and dementia. INTRODUCTIONThe microtubule-associated protein tau promotes neuronal cell polarization and axonal outgrowth; it is also necessary for maintaining axonal morphology and axonal transport (Caceres and Kosik, 1990;Esmaeli-Azad et al., 1994;Trinczek et al., 1999;Stamer et al., 2002). Alternatively, abnormal tau is the major component of neurofibrillary tangles, hallmark pathological features of Alzheimer's disease and related dementias.Mechanistically, tau acts by binding to microtubules directly and regulating their growing, shortening, and treadmilling dynamics (Drechsel et al., 1992;Panda et al., 1995Panda et al., , 1999Trinczek et al., 1995). Because tight regulation of microtubule dynamics and microtubule behavior can be critical to cell viability (Jordan et al., 1996;Goncalves et al., 2001), fine regulation of tau activity may be equally critical.Tau activity is regulated in part by alternative mRNA splicing, which leads to the expression of two families of tau isoforms, those containing four C-terminal repeats and those with three such repeats ( Figure 1A; Lee et al., 1988;Himmler, 1989). In vitro studies have shown that 4-repeat tau binds to, assembles, and stabilizes microtubules more effectively than 3-repeat tau (Butner and Kirschner, 1991;Gustke et al., 1994;Trinczek et al., 1995;Goode et al., 2000;Panda et al., 2003). However, there are limited data assessing the abilities of 3-or 4-repeat tau to modulate dynamics in a complex cellular environment.The importance of functional differences between 3-and 4-repeat tau is highlighted by two observations. First, altho...

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“…The longest isoform of tau in the human CNS contains a MTB region that contains four pseudo‐repeats (R1–R4) plus flanking proline‐rich regions (P1, P2, and P3; Gustke et al , 1994), a shorter (≈40 aa) C‐terminal tail, and a long (≈250 aa) flexible N‐terminal half of tau, which projects from the surface of microtubules in the MT‐bound state (Goode et al , 1997), and forms a polyelectrolyte brush around fibrillary aggregates of tau (Sillen et al , 2005; Wegmann et al , 2013). The lack of a fixed tertiary protein structure classifies tau as an intrinsically disordered protein (IDP).…”

Section: Introductionmentioning

confidence: 99%

Tau protein liquid–liquid phase separation can initiate tau aggregation

et al. 2018

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The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid–liquid phase separation (LLPS) under cellular conditions and that phase‐separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho‐tau isolated from human Alzheimer brain. Droplet‐like tau can also be observed in neurons and other cells. We found that tau droplets become gel‐like in minutes, and over days start to spontaneously form thioflavin‐S‐positive tau aggregates that are competent of seeding cellular tau aggregation. Since analogous LLPS observations have been made for FUS, hnRNPA1, and TDP43, which aggregate in the context of amyotrophic lateral sclerosis, we suggest that LLPS represents a biophysical process with a role in multiple different neurodegenerative diseases.

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Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly.

Cited by 259 publications

References 84 publications

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

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

Modulation of Microtubule Dynamics by Tau in Living Cells: Implications for Development and Neurodegeneration

Tau protein liquid–liquid phase separation can initiate tau aggregation

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