N-terminal truncation of microtubule associated protein tau dysregulates its cellular localization (original) (raw)
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Nuclear face of Tau: an inside player in neurodegeneration
Acta Neuropathologica Communications, 2023
Tau (Tubulin associated unit) protein is a major hallmark of Alzheimer's disease (AD) and tauopathies. Tau is predominantly an axonal protein with a crucial role in the stabilization and dynamics of the microtubules. Since the discovery of Tau protein in 1975, research efforts were concentrated on the pathophysiological role of Tau protein in the context of the microtubules. Although, for more than three decades, different localizations of Tau protein have been discovered e.g., in the nuclear compartments. Discovery of the role of Tau protein in various cellular compartments especially in the nucleus opens up a new fold of complexity in tauopathies. Data from cellular models, animal models, and the human brain indicate that nuclear Tau is crucial for genome stability and to cope with cellular distress. Moreover, it's nature of nuclear translocation, its interactions with the nuclear DNA/RNA and proteins suggest it could play multiple roles in the nucleus. To comprehend Tau pathophysiology and efficient Taubased therapies, there is an urgent need to understand whole repertoire of Tau species (nuclear and cytoplasmic) and their functional relevance. To complete the map of Tau repertoire, understanding of various species of Tau in the nucleus and cytoplasm, identification if specific transcripts of Tau, isoforms and post-translational modifications could foretell Tau's localizations and functions, and how they are modified in neurodegenerative diseases like AD, is urgently required. In this review, we explore the nuclear face of Tau protein, its nuclear localizations and functions and its linkage with Alzheimer's disease.
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
Nuclear Tau and Its Potential Role in Alzheimer's Disease
Tau protein, found in both neuronal and non-neuronal cells, forms aggregates in neurons that constitutes one of the hallmarks of Alzheimer's disease (AD). For nearly four decades, research efforts have focused more on tau's role in physiology and pathology in the context of the microtubules, even though, for over three decades, tau has been localised in the nucleus and the nucleolus. Its nuclear and nucleolar localisation had stimulated many questions regarding its role in these compartments. Data from cell culture, mouse brain, and the human brain suggests that nuclear tau could be essential for genome defense against cellular distress. However, its nature of translocation to the nucleus, its nuclear conformation and interaction with the DNA and other nuclear proteins highly suggest it could play multiple roles in the nucleus. To find efficient tau-based therapies, there is a need to understand more about the functional relevance of the varied cellular distribution of tau, identify whether specific tau transcripts or isoforms could predict tau's localisation and function and how they are altered in diseases like AD. Here, we explore the cellular distribution of tau, its nuclear localisation and function and its possible involvement in neurodegeneration.
Journal of Biological Chemistry, 2003
The accumulation of abnormal tau filaments is a pathological hallmark of many neurodegenerative diseases. In 1998, genetic analyses revealed a direct linkage between structural and regulatory mutations in the tau gene and the neurodegenerative disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Importantly, the FTDP-17 phenotype is transmitted in a dominant rather than a recessive manner. However, the underlying molecular mechanisms causing disease remain uncertain. The most common molecular mechanism generating dominant phenotypes is the loss of function of a multimeric complex containing both mutant and wild-type subunits. Therefore, we sought to determine whether tau might normally function as a multimer. We co-incubated 35 S-radiolabeled tau and biotinylated tau with taxol stabilized microtubules, at very low molar ratios of tau to tubulin. Subsequent covalent cross-linking followed by affinity-precipitation of the biotinylated tau revealed the formation of microtubule-dependent tau oligomers. We next used atomic force microscopy to independently assess this conclusion. Our results are consistent with the hypothesis that tau forms oligomers upon binding to microtubules. In addition to providing insights into normal tau action, our findings lead us to propose that one mechanism by which mutations in tau may cause cell death is through the formation of tau complexes containing mutant tau molecules in association with wild-type tau. These wildtype-mutant tau complexes may possess altered biological and/or biophysical properties that promote onset of the FTDP-17 phenotype, including neuronal cell death by either altering normal tau-mediated regulation of microtubule-dependent cellular functions and/or promoting the formation of pathological tau aggregates.
Nucleic acids research, 2018
Tauopathies such as Alzheimer's Disease (AD) are neurodegenerative disorders for which there is presently no cure. They are named after the abnormal oligomerization/aggregation of the neuronal microtubule-associated Tau protein. Besides its role as a microtubule-associated protein, a DNA-binding capacity and a nuclear localization for Tau protein has been described in neurons. While questioning the potential role of Tau-DNA binding in the development of tauopathies, we have carried out a large-scale analysis of the interaction of Tau protein with the neuronal genome under physiological and heat stress conditions using the ChIP-on-chip technique that combines Chromatin ImmunoPrecipitation (ChIP) with DNA microarray (chip). Our findings show that Tau protein specifically interacts with genic and intergenic DNA sequences of primary culture of neurons with a preference for DNA regions positioned beyond the ±5000 bp range from transcription start site. An AG-rich DNA motif was found ...
Journal of neurochemistry, 2016
Despite extensive structure-function analyses, the molecular mechanisms of normal and pathological tau action remain poorly understood. How does the C-terminal microtubule-binding region regulate microtubule dynamics and bundling? In what biophysical form does tau transfer trans-synaptically from one neuron to another, promoting neurodegeneration and dementia? Previous biochemical/biophysical work led to the hypothesis that tau can dimerize via electrostatic interactions between two N-terminal "projection domains" aligned in an anti-parallel fashion, generating a multivalent complex capable of interacting with multiple tubulin subunits. We sought to test this dimerization model directly. Native gel analyses of full-length tau and deletion constructs demonstrate that the N-terminal region leads to multiple bands, consistent with oligomerization. Ferguson analyses of native gels indicate that an N-terminal fragment (tau(45-230) ) assembles into heptamers/octamers. Ferguson a...
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...
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.