Tau antagonizes EB tracking at microtubule ends through a phosphorylation-dependent mechanism (original) (raw)
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Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects
Frontiers in Aging Neuroscience
Microtubules (MTs) play a fundamental role in many vital processes such as cell division and neuronal activity. They are key structural and functional elements in axons, supporting neurite differentiation and growth, as well as transporting motor proteins along the axons, which use MTs as support tracks. Tau is a stabilizing MT associated protein, whose functions are mainly regulated by phosphorylation. A disruption of the MT network, which might be caused by Tau loss of function, is observed in a group of related diseases called tauopathies, which includes Alzheimer's disease (AD). Tau is found hyperphosphorylated in AD, which might account for its loss of MT stabilizing capacity. Since destabilization of MTs after dissociation of Tau could contribute to toxicity in neurodegenerative diseases, a molecular understanding of this interaction and its regulation is essential.
Scientific Reports, 2015
Tau is a central player in Alzheimer's disease (AD) and related Tauopathies, where it is found as aggregates in degenerating neurons. Abnormal post-translational modifications, such as truncation, are likely involved in the pathological process. A major step forward in understanding the role of Tau truncation would be to identify the precise cleavage sites of the several truncated Tau fragments that are observed until now in AD brains, especially those truncated at the N-terminus, which are less characterized than those truncated at the C-terminus. Here, we optimized a proteomics approach and succeeded in identifying a number of new N-terminally truncated Tau species from the human brain. We initiated cell-based functional studies by analyzing the biochemical characteristics of two N-terminally truncated Tau species starting at residues Met11 and Gln124 respectively. Our results show, interestingly, that the Gln124-Tau fragment displays a stronger ability to bind and stabilize microtubules, suggesting that the Tau N-terminal domain could play a direct role in the regulation of microtubule stabilization. Future studies based on our new N-terminally truncated-Tau species should improve our knowledge of the role of truncation in Tau biology as well as in the AD pathological process. T au is a microtubule-associated protein (MAP) mainly found in neurons and expressed in the adult human brain as 6 isoforms (ranging from 352 to 441 amino acid residues in length), which are derived from a single gene, MAPT, by the alternative splicing of exons 2, 3 and 10 1. Tau is composed of an amino terminal acidic domain followed by two proline-rich domains and a microtubule-binding domain 2. The latter contains 3 or 4 microtubule-binding repeats, depending on whether the sequence encoded by exon 10 is included or not 3. Tau is primarily involved in the regulation of microtubule stability and dynamics as well as axonal transport 4,5. Besides its role as a MAP, Tau exhibits other cellular localizations and functions that have been less investigated 6-8. Tau proteins aggregate into filaments in a large group of neurodegenerative disorders referred to as Tauopathies, such as Alzheimer's Disease (AD) and Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17) 9. AD is the most common Tauopathy and form of dementia. One of its neuropathological hallmarks is neurofibrillary degeneration (NFD), characterized by aggregated Tau proteins. Studies have shown that the progression of NFD in cortical brain areas is closely correlated to cognitive impairment in AD, supporting a central role for Tau in AD pathology 10,11. As of now, the mechanisms leading to NFD and its progression are far from being elucidated. Nevertheless, the deregulation of Tau phosphorylation is a key event in the pathological process. Numerous studies suggest that abnormal phosphorylation impedes Tau binding to microtubules, leading on the one hand to the depolymerization and loss of the latter, and on the other hand to the formation of toxic aggregated Tau species 12. Truncation is another post-translational modification that could have an etiological role in Tau pathology. Numerous cell-based assays show that the truncation of either the C-terminal part of Tau or both the N-and C-terminal parts impacts its biochemical and functional properties and triggers a gain of toxic function 13-16. Moreover, animal models based on the expression of particular truncated Tau species are able to reproduce Tau pathology 16-18. The analysis of AD brains by western blotting (WB) and epitope mapping suggests the occurrence of cleavage sites in both the N-terminal and C-terminal parts of Tau proteins 19,20. While several Nand C-terminally truncated Tau species are observed in AD brains, only a limited number of specific Tau cleavage
Journal of neurochemistry, 2015
The axonal microtubule-associated protein (MAP) tau is a well-known regulator of microtubule stability in neurons. However, the putative interplay between tau and End-binding proteins 1 and 3 (EB1/3), the core microtubule plus-end tracking proteins (+TIPs), has not been elucidated yet. Here we show that a crosstalk between tau and EB1/3 exists in developing neuronal cells. Tau and EBs partially colocalize at extending neurites of N1E-115 neuroblastoma cells and axons of primary hippocampal neurons, as shown by confocal immunofluorescence analyses. Tau downregulation leads to a reduction of EB1/3 comet length, as observed in shRNA-stably depleted neuroblastoma cells and TAU-/- neurons. EB1/3 localization depends on the expression levels and localization of tau protein. Overexpression of tau at high levels induces EBs relocalization to microtubule bundles at extending neurites of N1E-115 cells. In differentiating primary neurons, tau is required for the proper accumulation of EBs at s...
Scientific reports, 2017
Tau pathology is associated with cognitive decline in Alzheimer's disease, and missense tau mutations cause frontotemporal dementia. Hyperphosphorylation and misfolding of tau are considered critical steps leading to tauopathies. Here, we determine how motifs controlling conformational changes in the microtubule-binding domain determine tau pathology in vivo. Human tau was overexpressed in the adult mouse forebrain to compare variants carrying residues that modulate tau propensity to acquire a β-sheet conformation. The P301S mutation linked to frontotemporal dementia causes tau aggregation and rapidly progressing motor deficits. By comparison, wild-type tau becomes heavily hyperphosphorylated, and induces behavioral impairments that do not progress over time. However, the behavioral defects caused by wild-type tau can be suppressed when β-sheet breaking proline residues are introduced in the microtubule-binding domain of tau. This modification facilitates tau interaction with mi...
2020
Tau is a microtubule-associated protein that regulates the stability of microtubules. The affinity of tau for microtubules is modulated by post-translational modifications, and the dysregulation of these events has been associated with the aberrant aggregation of tau in Alzheimer's disease and related tauopathies. Here, we use the metainference cryo-electron microscopy approach to determine an ensemble of structures representing the structure and dynamics of a tau-microtubule complex comprising an extended microtubule-binding region of tau (residues 202-395). We thus identify the ground state of the complex and a series of excited states of lower populations. An analysis of the interactions in these states of structures reveals positions in the tau sequence that are important to determine the overall stability of the tau-microtubule complex. This analysis leads to the identification of positions where phosphorylation and acetylation events have destabilising effects, which we va...
Atypical, non-standard functions of the microtubule associated Tau protein
Acta neuropathologica communications, 2017
Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau's role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer's disease (AD) brains. In recent years, however, research efforts identified new interaction partners and different sub-cellular localizations for Tau suggesting additional roles beyond its standard function as microtubule regulating protein. Moreover, despite the increasing research focus on AD over the last decades, Tau was only recently considered as a promising therapeutic target for the treatment and prevention of AD as well as for neurological pathologies beyond AD e.g. epilepsy, excitotoxicity, and environmental stress. This review will focus on atypical, non-standard roles of Tau on neuronal function and dysfunction in AD and other neurological pathologies providing novel insights about neuroplast...
European Journal of Neuroscience, 2007
Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains with Alzheimer's disease. The phosphorylation sites of tau are mainly localized in the proline-rich (residues 172-251) and C-terminal tail (residues 368-441) regions, which flank the microtubule-binding repeats. Here, we investigated the effects of tau phosphorylation at these distinct sites/regions on its activity of stimulating microtubule assembly and its selfaggregation. We found that tau phosphorylation at the proline-rich region by dual-specificity tyrosine-phosphorylated and -regulated kinase 1A inhibited its microtubule assembly activity moderately and promoted its self-aggregation slightly. Tau phosphorylation at the C-terminal tail region by glycogen synthase kinase-3β increased its activity and promoted its self-aggregation markedly. Tau phosphorylation at both regions plus the microtubule-binding region by cAMPdependent protein kinase diminished its activity (~70% inhibition) and disrupted microtubules. These studies reveal the differential regulation of tau's biological activity and self-aggregation by phosphorylation at various sites/regions.
Tau can switch microtubule network organizations: from random networks to dynamic and stable bundles
Molecular biology of the cell, 2018
In neurons, microtubule networks alternate between single filaments and bundled arrays under the influence of effectors controlling their dynamics and organization. Tau is a microtubule bundler that stabilizes microtubules by stimulating growth and inhibiting shrinkage. The mechanisms by which tau organizes microtubule networks remain poorly understood. Here, we studied the self-organization of microtubules growing in the presence of tau isoforms and mutants. The results show that tau's ability to induce stable microtubule bundles requires two hexapeptides located in its microtubule-binding domain and is modulated by its projection domain. Site-specific pseudophosphorylation of tau promotes distinct microtubule organizations: stable single microtubules, stable bundles, or dynamic bundles. Disease-related tau mutations increase the formation of highly dynamic bundles. Finally, cryo-electron microscopy experiments indicate that tau and its variants similarly change the microtubule...