Site‐Specific Hyperphosphorylation Inhibits, Rather than Promotes, Tau Fibrillization, Seeding Capacity, and Its Microtubule Binding

Haj‐Yahya, Mahmood; Gopinath, Pushparathinam; Rajasekhar, Kolla; Mirbaha, Hilda; Diamond, Marc I.; Lashuel, Hilal A.

doi:10.1002/anie.201913001

Cited by 67 publications

(51 citation statements)

References 38 publications

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“…56 The fact that pSer356 reduces the population of intermediates near the fibril like conformers is also consistent with recent in vitro experiments reporting that WT K18 develops seeding activity more rapidly than pSer356 K18 in the presence of heparin. 57 Another important aspect of our 5 µs MD simulations on each species is that the β-helix motif covering residues 336-354 displays a RMSD between 0.15 and 0.4 nm in 30% of the WT conformational ensemble, and this population decreases to 5% in the pSer356 ensemble. Figure S9 This result is important as the β-helix region has been identified in the prion-forming domain of HET-s and plays a crucial role for infection.…”

Section: Resultsmentioning

confidence: 99%

Tau R3–R4 Domain Dimer of the Wild Type and Phosphorylated Ser356 Sequences. I. In Solution by Atomistic Simulations

et al. 2020

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In Alzheimer’s disease, neurofibrillary lesions correlate with cognitive deficits and consist of inclusions of tau protein with cross-β structure. A stable dimeric form of soluble tau has been evidenced in the cells, but its high-resolution structure is missing in solution. We know, however, that cryo-electron microscopy (c-EM) of full-length tau in the brain of an individual with AD displays a core of eight β-sheets with a C-shaped architecture spanning the R3–R4 repeat domain, while the rest of the protein is very flexible. To address the conformational ensemble of the dimer, we performed atomistic replica exchange molecular dynamics simulations on the tau R3–R4 domain starting from the c-EM configuration. We find that the wild type tau R3–R4 dimer explores elongated, U-shaped, V-shaped, and globular forms rather than the C-shape. Phosphorylation of Ser356, pSer356, is known to block the interaction between the tau protein and the amyloid-β42 peptide. Standard molecular dynamics simulations of this phosphorylated sequence for a total of 5 μs compared to its wild type counterpart show a modulation of the population of β-helices and accessible topologies and a decrease of intermediates near the fibril-like conformers.

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Section: Resultsmentioning

confidence: 99%

Tau R3–R4 Domain Dimer of the Wild Type and Phosphorylated Ser356 Sequences. I. In Solution by Atomistic Simulations

et al. 2020

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“…Phosphorylation of Tau at different sites can alter its function. For example, phosphorylation at serine 262, within the microtubule-binding domain of Tau, most strongly attenuates Tau binding to microtubules (Fischer et al, 2009 ; Haj-Yahya et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Loss of DEK Expression Induces Alzheimer’s Disease Phenotypes in Differentiated SH-SY5Y Cells

Greene

Parks

Solomon

et al. 2020

Front. Mol. Neurosci.

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Alzheimer’s disease (AD) is the most common cause of dementia and is characterized by the buildup of β-amyloid plaques and neurofibrillary Tau tangles. This leads to decreased synaptic efficacy, cell death, and, consequently, brain atrophy in patients. Behaviorally, this manifests as memory loss and confusion. Using a gene ontology analysis, we recently identified AD and other age-related dementias as candidate diseases associated with the loss of DEK expression. DEK is a nuclear phosphoprotein with roles in DNA repair, cellular proliferation, and inhibiting apoptosis. Work from our laboratory determined that DEK is highly expressed in the brain, particularly in regions relevant to learning and memory, including the hippocampus. Moreover, we have also determined that DEK is highly expressed in neurons. Consistent with our gene ontology analysis, we recently reported that cortical DEK protein levels are inversely proportional to dementia severity scores in elderly female patients. However, the functional role of DEK in neurons is unknown. Thus, we knocked down DEK in an in vitro neuronal model, differentiated SH-SY5Y cells, hypothesizing that DEK loss would result in cellular and molecular phenotypes consistent with AD. We found that DEK loss resulted in increased neuronal death by apoptosis (i.e., cleaved caspases 3 and 8), decreased β-catenin levels, disrupted neurite development, higher levels of total and phosphorylated Tau at Ser262, and protein aggregates. We have demonstrated that DEK loss in vitro recapitulates cellular and molecular phenotypes of AD pathology.

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“…Despite consistent findings implicating PHF6 in the initiation of Tau aggregation, stabilization of Tau fibrils and the importance of the interaction of Y310 and I308 for Tau filament formation (35), there are no reports in the literature examining the potential impact of phosphorylation at this residue on the physiological and/or pathogenic properties of biologically-relevant full-length Tau proteoforms. This is possibly due to the lack of well-characterised pY310 specific antibodies and until recently the lack of methods for site-specific phosphorylation of Tau (57)(58)(59).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of the overlooked tyrosine 310 regulates the structure, aggregation, and microtubule- and lipid-binding properties of Tau

Ait-Bouziad

Chiki

Limorenko

et al. 2020

Preprint

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ABSTRACTThe microtubule-associated protein Tau is implicated in the pathogenesis of several neurodegenerative disorders, including Alzheimer’s disease. Increasing evidence suggests that post-translational modifications play critical roles in regulating Tau normal functions and its pathogenic properties in Tauopathies. Very little is known about how phosphorylation of tyrosine residues influences the structure, aggregation, and microtubule- and lipid-binding properties of Tau. In this work, we aimed to address this knowledge gap and determine the relative contribution of phosphorylation of one or several of the five tyrosine residues in Tau (Y18, Y29, Y197, Y310 and Y394) to the regulation of its biophysical, aggregation and functional properties. Towards this goal, we used a combination of site-specific mutagenesis and in vitro phosphorylation by c-Abl kinase to generate Tau species phosphorylated at all tyrosine residues, all tyrosine residues except Y310 or Y394 (pTau-Y310F, pTau-Y394F) and Tau phosphorylated only at Y310 or Y394 (4F\pY310 or 4F\pY394). Our results show that phosphorylation at all five tyrosine residues, multiple N-terminal tyrosine residues (Y18, Y29 and Y197) or site-specific phosphorylation at residue Y310, itself located in the microtubule-binding and aggregation-prone domain of Tau, was sufficient to abolish Tau aggregation and inhibit its microtubule- and lipid-binding properties. NMR studies demonstrated that these effects were mediated by a local decrease in β−sheet propensity of the PHF6 domain. Our findings underscore the unique role of Y310 phosphorylation in the regulation of Tau aggregation, microtubule and lipid interactions and highlight the importance of conducting further studies to elucidate its role in the regulation of Tau normal functions and its pathogenic properties.

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Site‐Specific Hyperphosphorylation Inhibits, Rather than Promotes, Tau Fibrillization, Seeding Capacity, and Its Microtubule Binding

Cited by 67 publications

References 38 publications

Tau R3–R4 Domain Dimer of the Wild Type and Phosphorylated Ser356 Sequences. I. In Solution by Atomistic Simulations

Tau R3–R4 Domain Dimer of the Wild Type and Phosphorylated Ser356 Sequences. I. In Solution by Atomistic Simulations

Loss of DEK Expression Induces Alzheimer’s Disease Phenotypes in Differentiated SH-SY5Y Cells

Phosphorylation of the overlooked tyrosine 310 regulates the structure, aggregation, and microtubule- and lipid-binding properties of Tau

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