Tau Structures

Ávila, Jesús; Jiménez, Juan S.; Sayas, Carmen Laura; Bolós, Marta; Zabala, Juan Carlos; Rivas, Germán; Hernández, Félix

doi:10.3389/fnagi.2016.00262

Cited by 97 publications

(92 citation statements)

References 121 publications

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“…Although tau is considered a natively unfolded protein [sometimes also called an intrinsically disordered protein (IDP)], its ability to adopt various structural states is important to its functions and pathological properties. Since the first report on tau structure in 1977 [38], there have been numerous approaches and reports addressing tau structure in various contexts (reviewed in [39]). While the intrinsically disordered nature of tau precludes the use of crystallographic methods, circular dichroism, nuclear magnetic resonance (NMR) spectroscopy, and more recently cryogenic Location of the projection domain, proline-rich domain, MTBDs, and the parts of tau protein encoded by the alternatively spliced exons 2, 3 and 10 are shown on top of the longest tau isoform (2N4R, 441 aa).…”

Section: Structural Plasticity and Aggregation Of Taumentioning

confidence: 99%

Mechanisms of secretion and spreading of pathological tau protein

Brunello

Merezhko

Uronen

et al. 2019

Cell. Mol. Life Sci.

207

185

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Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer's disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-tocell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.

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Section: Structural Plasticity and Aggregation Of Taumentioning

confidence: 99%

Mechanisms of secretion and spreading of pathological tau protein

Brunello

Merezhko

Uronen

et al. 2019

Cell. Mol. Life Sci.

207

185

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“…Under physiological condition, tau exists in an unfolded state, and 80% of the proteins interact with microtubule in neurons [22,26]. When tau is not interacting with other proteins, it may curl on its own, and this random curled state is believed important for preventing interactions with other tau proteins by masking the possible interacting sites [27,28]. The protein itself is bipolar; the N-terminal side is highly negatively charged in normal physiology, while the proline-rich domain and C-terminal end are positively charged, allowing it to interact with the negatively charged C-terminal of tubulins [22,29].…”

Section: Tau Structures and Functionsmentioning

confidence: 99%

Tauopathy

Ran¹,

Sang²,

Chang³

2019

Cognitive Disorders

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Tauopathy is a category of neurodegenerative diseases that are caused or associated with pathological tau protein. Some of the diseases are relatively common, which include Alzheimer's disease (AD) and various Parkinsonism (PD). Tau protein is a type of microtubule-associated protein (MAP), encoded by the gene MAPT (microtubule-associated protein tau). Normally, tau binds to microtubule, supporting the assembling and structure of cytoskeletons. However, in tauopathy, normal tau protein undergoes abnormal posttranslational modifications and detaches from microtubule; furthermore, they may aggregate forming paired helical filaments (PHF) or straight filaments (SF). Abundant PHF could be observed under microscope as fibrillary tangles. In this chapter, we will introduce the pathogenesis process of tauopathy with regard to the posttranslational modifications of the protein, the animal models, and the developing treatments against tauopathy from a clinical prospective.

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“…The six tau isoforms range from 352 to 441 amino acids. Tau isoforms vary in either having zero, one, or two N-terminal inserts (exons 2 and 3) and three or four repeats region at the C-terminal region (exon 10) (10, 11).…”

Section: Introductionmentioning

confidence: 99%

Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

Yadikar

Torres

Aiello

et al. 2019

Preprint

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26Tauopathies are a class of neurodegenerative disorders characterized by abnormal deposition of 27 post-translationally modified tau protein in the human brain. Tauopathies are associated with 28 Alzheimer's disease (AD), chronic traumatic encephalopathy (CTE), and other diseases. 29Hyperphosphorylation increases tau tendency to aggregate and forms neurofibrillary tangles 30 (NFT), a pathological hallmark of AD. In this study, okadaic acid (OA, 100 nM), a protein 31 phosphatase 1/2A inhibitor, was treated for 24h in mouse neuroblastoma (N2a) and differentiated 32 rat primary neuronal cortical cell cultures (CTX) to induce tau-hyperphosphorylation and 33 oligomerization as a cell-based tauopathy model. Following the treatments, the effectiveness of 34 different kinase inhibitors was assessed using the tauopathy-relevant tau antibodies through tau-35 immunoblotting, including the sites: pSer202/pThr205 (AT8), pThr181 (AT270), pSer202 (CP13), 36 pSer396/pSer404 (PHF-1), and pThr231 (RZ3). OA-treated samples induced tau phosphorylation 37 and oligomerization at all tested epitopes, forming a monomeric band (46-67 kDa) and oligomeric 38 bands (170 kDa and 240 kDa). We found that TBB (a casein kinase II inhibitor), AR and LiCl 39 (GSK-3 inhibitors), cyclosporin A (calcineurin inhibitor), and Saracatinib (Fyn kinase inhibitor) 40 caused robust inhibition of OA-induced monomeric and oligomeric p-tau in both N2a and CTX 41 culture. Additionally, a cyclin-dependent kinase 5 inhibitor (Roscovitine) and a calcium chelator 42 (EGTA) showed conflicting results between the two neuronal cultures.This study provides a 43 comprehensive view of potential drug candidates (TBB, CsA, AR, and Saracatinib), and their 44 efficacy against tau hyperphosphorylation and oligomerization processes. These findings warrant 45 further experimentation, possibly including animal models of tauopathies, which may provide a 46 putative Neurotherapy for AD, CTE, and other forms of tauopathy-induced neurodegenerative 47 diseases.48

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Tau Structures

Cited by 97 publications

References 121 publications

Mechanisms of secretion and spreading of pathological tau protein

Mechanisms of secretion and spreading of pathological tau protein

Tauopathy

Screening of Tau Protein Kinase Inhibitors in a Tauopathy-relevant cell-based model of Tau Hyperphosphorylation and Oligomerization

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