Synaptic Released Zinc Promotes Tau Hyperphosphorylation by Inhibition of Protein Phosphatase 2A (PP2A)

Sun, Xuying; Ye, Wei; Xiong, Yan; Wang, Xiao-Chuan; Xie, Ao-Ji; Wang, Xiulian; Yang, Yang; Wang, Qun; Lu, Youming; R, Liu; Wang, Jian‐Zhi

doi:10.1074/jbc.m111.309070

Cited by 120 publications

(83 citation statements)

References 48 publications

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“…This suggests that zinc can inhibit PP2A by competing with iron and magnesium. In vitro, 1 μM zinc leads to 87% inhibition of PP2A activity [31], and zinc released during synaptic activity of glutamatergic neurons inhibits PP2A in cultured slices from the rat hippocampus [32]. PP2A refers to an important family of heterotrimeric serine/threonine phosphatases that represents a major contribution of the serine/threonine phosphatase activity in eukaryotic cells participating in a variety of signaling pathways involved in diverse cellular processes such as control of the cell cycle, apoptosis and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

Nuttall

Supasai

Kha

et al. 2015

The Journal of Nutritional Biochemistry

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Section: Discussionmentioning

confidence: 99%

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

Nuttall

Supasai

Kha

et al. 2015

The Journal of Nutritional Biochemistry

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“…GSK3b activity was assessed using a commercial detection kit (Sigma-Aldrich Inc) as previously described (Jiang et al, 2014d). Meanwhile, PP2A activity was measured as described by Sun et al (2012).…”

Section: Measurement Of Glycogen Synthase Kinase 3b and Protein Phospmentioning

confidence: 99%

Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice

Jiang

Tan

Zhu

et al. 2015

Neurobiology of Aging

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“…PP-2A activity is regulated by endogenous protein inhibitors. PP-2A is considered a major tau phosphatase because it binds to tau and directly or indirectly regulates its phosphorylation by regulating GSK-3 activity [48][49][50][51][52][53] . In the human brain, PP-2A accounts for 70% of the tau phosphatase activity and in the AD brain this enzyme activity is reduced [47] .…”

mentioning

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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Synaptic Released Zinc Promotes Tau Hyperphosphorylation by Inhibition of Protein Phosphatase 2A (PP2A)

Cited by 120 publications

References 48 publications

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

Gestational marginal zinc deficiency impaired fetal neural progenitor cell proliferation by disrupting the ERK1/2 signaling pathway

Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice

Tau-induced neurodegeneration: mechanisms and targets

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