Systemic and network functions of the microtubule-associated protein tau: Implications for tau-based therapies

Bakota, Lidia; Ussif, Abdala Mumuni; Jeserich, G.; Brandt, Roland

doi:10.1016/j.mcn.2017.03.003

Cited by 28 publications

(24 citation statements)

References 103 publications

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“…However, it is notable that the phenotypic changes exhibited by different lines of tau-deficient mice have proved to be somewhat inconsistent due to several possible confounding factors (reviewed in [27]). First, changes induced by the absence of tau during neuronal development may be variably compensated by increased expression of other microtubule-associated proteins, including MAP1A.…”

Section: Tau and Neuronal Activitymentioning

confidence: 99%

Roles of tau protein in health and disease

2017

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Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies. Recent advances in our understanding of the multiple functions and different locations of tau inside and outside neurons have revealed novel insights into its importance in a diverse range of molecular pathways including cell signalling, synaptic plasticity, and regulation of genomic stability. The present review describes the physiological and pathophysiological properties of tau and how these relate to its distribution and functions in neurons. We highlight the post-translational modifications of tau, which are pivotal in defining and modulating tau localisation and its roles in health and disease. We include discussion of other pathologically relevant changes in tau, including mutation and aggregation, and how these aspects impinge on the propensity of tau to propagate, and potentially drive neuronal loss, in diseased brain. Finally, we describe the cascade of pathological events that may be driven by tau dysfunction, including impaired axonal transport, alterations in synapse and mitochondrial function, activation of the unfolded protein response and defective protein degradation. It is important to fully understand the range of neuronal functions attributed to tau, since this will provide vital information on its involvement in the development and pathogenesis of disease. Such knowledge will enable determination of which critical molecular pathways should be targeted by potential therapeutic agents developed for the treatment of tauopathies.

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Section: Tau and Neuronal Activitymentioning

confidence: 99%

Roles of tau protein in health and disease

2017

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“…Tau has been reported to have a number of interacting partners, under normal and pathogenic conditions, which are comprehensively reviewed elsewhere (Mandelkow and Mandelkow, 2012;Bakota et al, 2017). Based on numerous studies, tau is an important MAP necessary for the development and maintenance of a neuron; however, tau-null mice are viable and display increasing cognitive impairments with age (Harada et al, 1994;Ikegami et al, 2000;Fujio et al, 2007;Lei et al, 2012).…”

Section: Taumentioning

confidence: 99%

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

Ramkumar

Jong

Ori-McKenney

2017

Developmental Dynamics

151

111

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Classical microtubule-associated proteins (MAPs) were originally identified based on their co-purification with microtubules assembled from mammalian brain lysate. They have since been found to perform a range of functions involved in regulating the dynamics of the microtubule cytoskeleton. Most of these MAPs play integral roles in microtubule organization during neuronal development, microtubule remodeling during neuronal activity, and microtubule stabilization during neuronal maintenance. As a result, mutations in MAPs contribute to neurodevelopmental disorders, psychiatric conditions, and neurodegenerative diseases. MAPs are post-translationally regulated by phosphorylation depending on developmental time point and cellular context. Phosphorylation can affect the microtubule affinity, cellular localization, or overall function of a particular MAP and can thus have profound implications for neuronal health. Here we review MAP1, MAP2, MAP4, MAP6, MAP7, MAP9, tau, and DCX, and how each is regulated by phosphorylation in neuronal physiology and disease. Developmental Dynamics 247:138-155,

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“…Recent work suggests that disease-related phosphorylation does not cause tau to fall off microtubules as the off-rate is unaffected by pseudophosphorylation at the PHF1 site (i.e., S396 and S404), but may reduce microtubule binding by decreasing the on-rate (Niewidok et al, 2016 ). The highly dynamic conformational flexibility of tau likely facilitates its interaction with a large repertoire of binding partners (Jeganathan et al, 2006 ; Uversky, 2015 ; Stern et al, 2017 ) (reviewed in Bakota et al, 2017 ). Further, tau's role as a scaffolding protein and the recruitment of phosphotransferases to the microtubule cystoskeleton associated with this function could in turn be subject to phosphoregulation.…”

Section: Pathogenic Mechanisms Linking Abnormal Tau To Axonopathymentioning

confidence: 99%

Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms

et al. 2017

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Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical in vitro evidence fueled the widespread notion that microtubule stabilization represents tau's primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability. However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy.

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Systemic and network functions of the microtubule-associated protein tau: Implications for tau-based therapies

Cited by 28 publications

References 103 publications

Roles of tau protein in health and disease

Roles of tau protein in health and disease

ReMAPping the microtubule landscape: How phosphorylation dictates the activities of microtubule‐associated proteins

Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms

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