Post-translational modifications of tau protein: Implications for Alzheimer's disease

Martin, Ludovic; Latypova, Xénia; Terro, Faraj

doi:10.1016/j.neuint.2010.12.023

Cited by 527 publications

(467 citation statements)

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“…As described above, these post-translational modifi cations may modulate the formation of tau-containing neurofi brillary tangles and therefore may be important in the regulation of AD [63] . The proteins that are known to be involved in both the fusion and fission of mitochondria are nuclear-encoded and targeted to the organelle after expression.…”

Section: Mitochondrial Involvement With Taumentioning

confidence: 98%

“…T h e m e c h a n i s m l e a d i n g n o r m a l t a u t o b e c o m e hyperphosphorylated remains unknown and posttranslational modifications besides phosphorylation could regulate tau function and aggregation [58] , such as ubiquitination [59] , glycation [60] , glycosylation [61] , nitration [62] , polyamination [63] , proteolysis [64] , acetylation [58] , and methylation [65] .…”

Section: Other Post-translational Modifi Cationsmentioning

confidence: 99%

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Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

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The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

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Section: Mitochondrial Involvement With Taumentioning

confidence: 98%

Section: Other Post-translational Modifi Cationsmentioning

confidence: 99%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

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“…In addition to phosphorylation, tau is also subject to a number of other covalent modifications, such as ubiquitination, sumoylation, acetylation, and glycosylation, all affecting its biological activities [49,50] reviewed in [10].…”

Section: Posttranslational Modifications Influencing Tau Toxicitymentioning

confidence: 99%

Signaling pathways and posttranslational modifications of tau in Alzheimer's disease: the humanization of yeast cells

Heinisch¹,

Brandt²

2016

MIC

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In the past decade, yeast have been frequently employed to study the molecular mechanisms of human neurodegenerative diseases, generally by means of heterologous expression of genes encoding the relevant hallmark proteins. However, it has become evident that substantial posttranslational modifications of many of these proteins are required for the development and progression of potentially disease relevant changes. This is exemplified by the neuronal tau proteins, which are critically involved in a class of neurodegenerative diseases collectively called tauopathies and which includes Alzheimer's disease (AD) as its most common representative. In the course of the disease, tau changes its phosphorylation state and becomes hyperphosphorylated, gets truncated by proteolytic cleavage, is subject to O-glycosylation, sumoylation, ubiquitinylation, acetylation and some other modifications. This poses the important question, which of these posttranslational modifications are naturally occurring in the yeast model or can be reconstituted by heterologous gene expression. Here, we present an overview on common modifications as they occur in tau during AD, summarize their potential relevance with respect to disease mechanisms and refer to the native yeast enzyme orthologs capable to perform these modifications. We will also discuss potential approaches to humanize yeast in order to create modification patterns resembling the situation in mammalian cells, which could enhance the value of Saccharomyces cerevisiae and Kluyveromyces lactis as disease models.

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“…Finally, hyperphosphorylation of Tau and phosphorylation of α-synuclein and ataxin-1 has been shown to enhance their aggregation. Recently, other posttranslational modifications such as oxidation, sumoylation, ubiquitination or nitration have also been implicated in the aggregation of Tau, α-synuclein and polyglutamine-rich proteins (Beyer, 2006, Martin, L. et al, 2011, Pennuto et al, 2009). In addition, glycosylation affects the processing of APP (Georgopoulou et al, 2001).…”

Section: Protein Aggregation and Neurotoxicitymentioning

confidence: 99%