Tau in physiology and pathology

Wang, Yipeng; Mandelkow, Eckhard

doi:10.1038/nrn.2015.1

Cited by 1,669 publications

(1,731 citation statements)

References 225 publications

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“…Phosphorylation has been extensively studied in the context of tau pathology (Mandelkow et al ., 1995; Wang & Mandelkow, 2016), but due to the multiplicity of phosphorylation sites in the protein, the site‐specific impact of phosphorylation on tau biology is not well understood. We chose to analyze the effect of mutations that mimic phosphorylation at specific residues that form part of the epitopes of antibodies elevated in AD or for which an aggregation propensity has been described (Biernat & Mandelkow, 1999; Chang et al ., 2011; Combs et al ., 2011; Kiris et al ., 2011; Prokopovich et al ., 2017, 50).…”

Section: Resultsmentioning

confidence: 99%

“…Understanding differences in this dual interplay between different forms of tau and the autophagic pathways may help to discover why some tau modifications contribute to pathogenicity while others only increase disease risk (Wang & Mandelkow, 2016). Similarly, in light of the extensive repertoire of posttranslational modifications already described for this protein (Prokopovich et al ., 2017), a systematic analysis of the impact of these modifications on different aspects of tau biology, including its turnover by selective forms of autophagy as investigated in this study, should help to clarify the physiological regulation of tau and the basis of its toxicity in the aging brain.…”

Section: Discussionmentioning

confidence: 99%

“…We wondered whether different tau mutations may also impact tau clearance differently. Our groups and others have shown the degradation of wild‐type forms of tau through the ubiquitin/proteasome system and through autophagy and failure to degrade some mutant forms of tau through these pathways (Lee et al ., 2013; Holtzman et al ., 2016; Wang & Mandelkow, 2016). However, the degradation pathways of different physiological tau isoforms and the effect of disease‐related point mutations and posttranslational modifications on tau degradation remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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SummaryLoss of neuronal proteostasis, a common feature of the aging brain, is accelerated in neurodegenerative disorders, including different types of tauopathies. Aberrant turnover of tau, a microtubule‐stabilizing protein, contributes to its accumulation and subsequent toxicity in tauopathy patients’ brains. A direct toxic effect of pathogenic forms of tau on the proteolytic systems that normally contribute to their turnover has been proposed. In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in tau or known to promote its aggregation. Interestingly, although most mutations markedly reduced degradation of tau through autophagy, the step of this process preferentially affected varies depending on the type of tau mutation. Overall, our studies unveil a complex interplay between the multiple modifications of tau and selective forms of autophagy that may determine its physiological degradation and its faulty clearance in the disease context.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interplay of pathogenic forms of human tau with different autophagic pathways

et al. 2017

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“…Various post‐translational modifications appear to affect the activity of tau in diverse contexts, among which the phosphorylation on tau protein is critically highlighted (Iqbal et al., 2016). Tau phosphorylation is reduced during embryogenesis, resulting in increased neuronal plasticity in the neonatal nervous systems (Wang & Mandelkow, 2016). Multiple kinases are capable of inducing tau phosphorylation, including GSK3β, CDK5 (cyclin‐dependent kinase 5), PKA (cAMP‐dependent protein kinase), and MAPK1 (mitogen‐activated protein kinase 1).…”

Section: Pathological Contributions Of the Ubiquitin–proteasome Systementioning

confidence: 99%

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

et al. 2018

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Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

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“…Interestingly, the latter type of lesion also represents the main pathological signature of a large group of less investigated neurodegenerative diseases collectively called tauopathies. In general, human tauopathies, which among others include progressive supranuclear palsy (PSP), Pick's disease, and corticobasal degeneration, display progressive accumulation of hyperphosphorylated microtubule‐associated protein tau and tau pathology together with behavioral impairments and loss in synaptic integrity without any Aβ deposits (Spillantini & Goedert, 2013; Wang & Mandelkow, 2016). …”

Section: Introductionmentioning

confidence: 99%

Brain 5‐lipoxygenase over‐expression worsens memory, synaptic integrity, and tau pathology in the P301S mice

2017

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SummaryProgressive accumulation of highly phosphorylated tau protein isoforms is the main feature of a group of neurodegenerative diseases collectively called tauopathies. Data from human and animal models of these diseases have shown that neuroinflammation often accompanies their pathogenesis. The 5‐lipoxygenase (5LO) is an enzyme widely expressed in the brain and a source of potent pro‐inflammatory mediators, while its pharmacological inhibition modulates the phenotype of a tau transgenic mouse model, the htau mice. By employing an adeno‐associated viral vector system to over‐express 5LO in the brain, we examined its contribution to the behavioral deficits and neuropathology in a different transgenic mouse model of tauopathy, the P301S mouse line. Compared with controls, 5LO‐targeted gene brain over‐expression in these mice resulted in a worsening of behavioral and motor deficits. Over‐expression of 5LO resulted in microglia and astrocyte activation and significant synaptic pathology, which was associated with a significant elevation of tau phosphorylation at specific epitopes, tau insoluble fraction, and activation of the cdk5 kinase. In vitro studies confirmed that 5LO directly modulates tau phosphorylation at the same epitopes via the cdk5 kinase pathway. These data demonstrate that 5LO plays a direct role in tau phosphorylation and is an active player in the development of the entire tau phenotype. They provide further support to the hypothesis that 5LO is a viable therapeutic target for the treatment and/or prevention of human tauopathy.

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Tau in physiology and pathology

Cited by 1,669 publications

References 225 publications

Interplay of pathogenic forms of human tau with different autophagic pathways

Interplay of pathogenic forms of human tau with different autophagic pathways

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

Brain 5‐lipoxygenase over‐expression worsens memory, synaptic integrity, and tau pathology in the P301S mice

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