Tyrosine Nitration within the Proline-Rich Region of Tau in Alzheimer's Disease

Reyes, Juan F.; Fu, Yifan; Vana, Laurel; Kanaan, Nicholas M.; Binder, Lester I.

doi:10.1016/j.ajpath.2011.01.030

Cited by 49 publications

(43 citation statements)

References 49 publications

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“…However, NO and peroxynitrite are also known to cause nitroso-oxidative damage under inflammatory conditions [29]. The observed opposing roles of NO effectors, such as peroxynitrite in induction of tissue damage of the CNS [29] and AD pathologies (Aβ aggregation and tau modification [30,31]) vs. GSNO in inhibitions of Aβ synthesis, inflammation, cognitive deficit [6,32], and tau hyperphosphorylation suggest GSNO as a neuroprotective effector of NO as compared to degenerating role of peroxynitrite. AD involves chronic inflammation and oxidative stress [33].…”

Section: Resultsmentioning

confidence: 99%

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Annamalai

Won

Choi

et al. 2015

Biochemical and Biophysical Research Communications

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Hyperphosphorylation and polymerization of microtubule-associated protein tau into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer’s disease (AD). Here we report that neuronal tau hyperphosphorylation under AD conditions is regulated by Snitrosoglutathione (GSNO), an endogenous nitric oxide carrier molecule. In cultured rat cortical primary neurons, we observed that GSNO treatment decreased the β-amyloid (Aβ25–35)-induced pathological tau hyperphosphorylation (Ser396, Ser404, and Ser202/Thr205). The decreased tau hyperphosphorylation correlated with decreased activity of calpain and decreased p35 proteolysis into p25 and Cdk5 activation. GSNO treatment also attenuated the Aβ25–35-induced activation of GSK-3β which is known to play critical role in tau hyperphosphorylation in addition to Cdk5. Consistent with above studies using cultured neurons, we also observed that systemic GSNO treatment of transgenic mouse model of AD (APPSw/PS1dE9) attenuated calpain-mediated p35 proteolysis and Cdk5/GSK-3β activities as well as tau hyperphosphorylation. In addition, GSNO treatment provided neuro- and cognitive protection in APPSw/PS1dE9 mice. This study describing the GSNO-mediated regulation of tau hyperphosphorylation and cognitive function, for the first time, suggests for therapeutic potential of GSNO as neuro- and cognitive-protective agent for AD.

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Section: Resultsmentioning

confidence: 99%

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Annamalai

Won

Choi

et al. 2015

Biochemical and Biophysical Research Communications

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“…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%

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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“…In AD patients, Tau nitration occurs selectively at Y18 and Y29, and to lesser extent at Y197 and Y394 [133]. Tau nitration at Y197 and Y18 has been reported to enhance disease progression in a range of neurodegenerative disorders [134], whereas nitration at Y29 appears to be a specific characteristic of AD [133]. Similarly, the abundant neuronal protein α-synuclein has been observed to form intracellular aggregates in patients with AD, PD or various ‘synucleinopathies’, perhaps as a consequence of protein nitration at tyrosine residues Y39, Y125, Y133 and Y136.…”

Section: Introductionmentioning

confidence: 99%

Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling

Adav

2016

Mol Brain

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Dementia is a syndrome associated with a wide range of clinical features including progressive cognitive decline and patient inability to self-care. Due to rapidly increasing prevalence in aging society, dementia now confers a major economic, social, and healthcare burden throughout the world, and has therefore been identified as a public health priority by the World Health Organization. Previous studies have established dementia as a ‘proteinopathy’ caused by detrimental changes in brain protein structure and function that promote misfolding, aggregation, and deposition as insoluble amyloid plaques. Despite clear evidence that pathological cognitive decline is associated with degenerative protein modifications (DPMs) arising from spontaneous chemical modifications to amino acid side chains, the molecular mechanisms that promote brain DPMs formation remain poorly understood. However, the technical challenges associated with DPM analysis have recently become tractable due to powerful new proteomic techniques that facilitate detailed analysis of brain tissue damage over time. Recent studies have identified that neurodegenerative diseases are associated with the dysregulation of critical repair enzymes, as well as the misfolding, aggregation and accumulation of modified brain proteins. Future studies will further elucidate the mechanisms underlying dementia pathogenesis via the quantitative profiling of the human brain proteome and associated DPMs in distinct phases and subtypes of disease. This review summarizes recent developments in quantitative proteomic technologies, describes how these techniques have been applied to the study of dementia-linked changes in brain protein structure and function, and briefly outlines how these findings might be translated into novel clinical applications for dementia patients. In this review, only spontaneous protein modifications such as deamidation, oxidation, nitration glycation and carbamylation are reviewed and discussed.

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Tyrosine Nitration within the Proline-Rich Region of Tau in Alzheimer's Disease

Cited by 49 publications

References 49 publications

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Tau-induced neurodegeneration: mechanisms and targets

Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling

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