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Phosphorylation of Thr231 slightly differentiates structure and interactions of cis- and trans-tau226-236 peptide hexamers
MENGQingqing, ZENGXincheng, SUYuhong, BAIGanggang, NussinovRuth, MABuyong
Chinese Journal of Alzheimer's Disease and Related Disorders ›› 2020, Vol. 3 ›› Issue (4) : 258-266.
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Abbreviation (ISO4): Chinese Journal of Alzheimer's Disease and Related Disorders
Editor in chief: Jun WANG
PDF(957 KB)
Phosphorylation of Thr231 slightly differentiates structure and interactions of cis- and trans-tau226-236 peptide hexamers
Objective: Investigate the effects of pT231 on the structure and peptide interaction in cis- and trans- tau oligomers, to examine their possible toxic mechanisms in Alzheimer's disease. Methods: Using replica-exchange molecular dynamics simulations, we studied the cis- and trans- hexamers of Tau225-246 fragment. The 56 replicas were simulated using NAMD program and CHARMM36 force field with GB model, from 300K to 450 K. Each replica was simulated for 200 ns, with total 11200 ns simulation time. Results: Interestingly, the backbone hydrogen bonds involving T231P232 had higher frequencies, indicated that they were the local interaction hot spots even before T231 phosphorylation. The backbone hydrogen bonds were more populous in trans- than in cis- tau hexamer. The 226VAVVR231T fragment had about 4%~10% β structure, more in trans- than in cis-hexamer. Although that the peptide N- to C- terminal distances were longer in trans-tau peptide, the cis- and trans-tau hexamers had similar solvent-accessible-surface areas and radius of gyrations. The Thr231phosphorylation abolished most backbone hydrogen bonds and β structures in cis-tau hexamer, but had less effects on trans-tau hexamer. The phosphate group formed salt bridge mostly with Arg230 in both cis- and trans-hexamer. However, phosphate preferd to form hydrogen bond with amide hydrogen of Arg230 in cis-hexamer, while in trans-hexamer the phosphate binds more to amide hydrogen of Lys234. The most decisive effects of T231 phosphorylation could be the exposed hydrophobic surface areaof VAVV, which increased about 100 Å2 after phosphorylation in cis-hexamer. But these areas were similar for trans-hexamer before and after T231 phosphorylation. Conclusion: Thr231 phosphorylation has different effects on the structure and chemical interaction in cis- and trans- Tau226-236hexamer. But there is no clear-cut difference that can link the local structure change to the toxicity of the tau oligomer. The differentiate effects of phosphorylation on the hydrophobic surface area of VAVV in cis- and trans- tau hexamer and the longer end-to-end distance of trans-tau226-236peptide need to be examined further in full length tau monomer and oligomers.
Alzheimer's disease / Tau protein / Amyloidosis / Phosphorylation / Molecular dynamics simulation
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The aggregation of the protein tau into amyloid fibrils is known to be involved in the causation of the neurodegenerative tauopathies and the progression of cognitive decline in Alzheimer's disease. This review surveys the mechanism of tau aggregation with special emphasis on the information obtained from biochemical and biophysical studies. First, tau is described from a structure-function perspective. Subsequently, the connection of tau to neurodegeneration is explained, and a description of the tau amyloid fibril is provided. Lastly, studies of the mechanism of tau fibril formation are reviewed, and the physiological significance of these studies with reference to how they can clarify many aspects of disease progression is described. The aim of this review is to underscore how mechanistic studies reveal the complexity of the tau fibril formation pathway and the plethora of species populated on or off the pathway of aggregation, and how this information can be beneficial in the design of inhibitors or drugs that ameliorate neurodegeneration.
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Pathological accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles, is a major hallmark of Alzheimer's disease, the most prevalent neurodegenerative condition worldwide. In addition to Alzheimer's disease, a number of neurodegenerative diseases, called tauopathies, are characterized by the accumulation of aggregated tau in a variety of brain regions. While tau normally plays an important role in stabilizing the microtubule network of the cytoskeleton, its dissociation from microtubules and eventual aggregation into pathological deposits is an area of intense focus for therapeutic development. Here we discuss the known cellular factors that affect tau aggregation, from post-translational modifications to molecular chaperones.
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Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.
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Tau is a microtubule-associated protein involved in the regulation of axonal microtubules in neurons. In pathological conditions, it forms fibrils that are molecular hallmarks of neurological disorders known as tauopathies. In the last 2 years, cryo-EM has given unprecedented high-resolution views of Tau in both physiological and pathological conditions. We review here these new findings and put them into the context of the knowledge about Tau before this structural breakthrough. The first structures of Tau fibrils, a molecular hallmark of Alzheimer's disease (AD), were based on fibrils from the brain of an individual with AD and, along with similar patient-derived structures, have set the gold standard for the field. Cryo-EM structures of Tau fibers in three distinct diseases, AD, Pick's disease, and chronic traumatic encephalopathy, represent the end points of Tau's molecular trajectory. We propose that the recent Tau structures may call for a re-examination of databases that link different Tau variants to various forms of dementia. We also address the question of how this structural information may link Tau's functional and pathological aspects. Because this structural information on Tau was obtained in a very short period, the new structures should be viewed in light of earlier structural observations and past and present functional data to shed additional light on Tau function and dysfunction.© 2019 Lippens and Gigant.
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The paired helical filament, the principal constituent of the neurofibrillary tangles characteristic of Alzheimer disease, is shown to consist of two structurally distinct parts. An external fuzzy region can be removed by Pronase treatment to leave a Pronase-resistant morphologically recognizable core. Scanning transmission electron microscopy gives an estimate for the mass per unit length as 79 kDa.nm-1 before Pronase treatment and 65 kDa.nm-1 after treatment. The fuzzy region carries all the epitopes recognized by two different antisera against microtubule-associated protein tau. By contrast, a monoclonal antibody (mAb) we have raised to paired helical filament cores (mAb 423) decorates Pronase-treated filaments much more strongly than it does untreated ones. We have shown in previous papers that the epitope recognized by mAb 423 is carried by a central 9.5-kDa fragment of tau protein, which therefore forms part of the Pronase-resistant core structure. The remainder of the tau protein incorporated into the filaments must contribute part, if not all, of the fuzzy region. The mass per unit length measurements imply that the three-domain structural subunit of the core that we visualized previously by image reconstruction has a molecular mass of approximately equal to 100 kDa.
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Bipolar disorder is a complex neuropsychiatric disorder, characterized by intermittent episodes of mania and depression. Recent studies have indicated argyrophilic grains, composed of hyperphosphorylated tau, are observable in postmortem brains of bipolar patients. It remains uncertain how tau hyperphosphorylation results in neurodegeneration upon the disease. Recent studies have demonstrated that phosphorylated tau at Thr231 exists in two distinct cis and trans conformations, in which cis pT231-tau is highly neurotoxic and acts as an early driver of tauopathy in several neurodegenerative diseases. We herein employed an in vitro model, which resembles some aspects of bipolar disorder, to study the cis p-tau mediatory role. We established GSK3β overexpressing SH-SY5Y cells and examined cell viability, cis p-tau formation, and lithium effects by immunofluorescence and flow cytometry. We found an increase in cis p-tau levels as well as viability decrease in the cell model. Furthermore, we discovered that lithium treatment inhibits cis p-tau formation, resulting in diminished cell death. We also examined BD and healthy human brain samples and detected cis p-tau in the patients' brains. Our results show that tauopathy, observed in bipolar disorder, is being mediated through cis p-tau and that a conformer could be the cause of neurodegeneration upon the disease. Our findings would suggest novel therapeutic target to fight the devastating disorder.
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Neurodegenerative disease is one of the greatest health concerns today and with no effective treatment in sight, it is crucial that researchers find a safe and successful therapeutic. While neurofibrillary tangles are considered the primary tauopathy hallmark, more evidence continues to come to light to suggest that soluble, intermediate tau aggregates--tau oligomers--are the most toxic species in disease. These intermediate tau species may also be responsible for the spread of pathology, suggesting that oligomeric tau may be the best therapeutic target. Here, we summarize results for the modulation of tau by molecular chaperones, small molecules and aggregation inhibitors, post-translational modifications, immunotherapy, other techniques, and future directions.
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The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/.Copyright 2004 Wiley Periodicals, Inc.
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Traumatic spinal cord injury (SCI) can result in substantial neurological impairment along with significant emotional and psychological distress. It is clear that there is profound neurodegeneration upon SCI, gradually spread to other spinal cord regions and brain areas. Despite extensive considerations, it remains uncertain how pathogenicity diffuses in the cord. It has been reported that tau protein abnormal hyperphosphorylation plays a central role in neurodegeneration triggered by traumatic brain injury (TBI). Tau is a microtubule-associated protein, heavily implicated in neurodegenerative diseases. Importantly, tau pathology spreads in a traumatic brain in a timely manner. In particular, we have recently demonstrated that phosphorylated tau at Thr231 exists in two distinct cis and trans conformations, in which that cis P-tau is extremely neurotoxic, has a prion nature, and spreads to various brain areas and cerebrospinal fluid (CSF) upon trauma. On the other hand, tau pathology, in particular hyperphosphorylation at Thr231, has been observed upon SCI. Taken these together, we conclude that cis pT231-tau may accumulate and spread in the spinal cord as well as CSF and diffuse tau pathology in the central nervous system (CNS). Moreover, antibody against cis P-tau can target intracellular cis P-tau and protect pathology spreading. Thus, considering cis P-tau as a driver of tau pathology and neurodegeneration upon SCI would open new windows toward understanding the disease development and early biomarkers. Furthermore, it would help us develop effective therapies for SCI patients.
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Traumatic brain injury (TBI) is characterized by acute neurological dysfunction and associated with the development of chronic traumatic encephalopathy (CTE) and Alzheimer's disease. We previously showed that cis phosphorylated tau (cis P-tau), but not the trans form, contributes to tau pathology and functional impairment in an animal model of severe TBI. Here we found that in human samples obtained post TBI due to a variety of causes, cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Using mouse models of severe or repetitive TBI, we showed that cis P-tau elimination with a specific neutralizing antibody administered immediately or at delayed time points after injury, attenuates the development of neuropathology and brain dysfunction during acute and chronic phases including CTE-like pathology and dysfunction after repetitive TBI. Thus, cis P-tau contributes to short-term and long-term sequelae after TBI, but is effectively neutralized by cis antibody treatment.
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