Zinc induces protein phosphatase 2A inactivation and tau hyperphosphorylation through Src dependent PP2A (tyrosine 307) phosphorylation

Xiong, Yan; Jing, Xiaopeng; Zhou, Xin‐Wen; Wang, Xiulian; Yang, Yang; Sun, Xuying; Qiu, Mei; Cao, Fuliang; Lu, Youming; R, Liu; Wang, Jian‐Zhi

doi:10.1016/j.neurobiolaging.2012.07.003

Cited by 109 publications

(73 citation statements)

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“…This could occur through altered PRKC activity or through inhibition by PP2A, as OCLN threonine phosphorylation can be directly inhibited by the activity of PP2A (30). Zinc is capable of inactivating PP2A through a src-dependent pathway (36). Loss of ZIP could lead to constitutively elevated PP2A activity, OCLN dephosphorylation and impaired assembly of OCLN at the TJ.…”

Section: Discussionmentioning

confidence: 99%

Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function

Guthrie

Aydemir

Troche

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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is a zinc transport protein with high expression in the small intestine and liver. Zip14 is upregulated during endotoxemia and leads to increased liver zinc content and transient hypozinemia. Since body zinc status and inflammation are associated with changes in intestinal permeability, we hypothesized that ZIP14 may influence intestinal permeability. Wild-type (WT) and Zip14 knockout (KO) mice were used to determine ZIP14-associated intestinal zinc metabolism and effects on permeability. Fractionation of plasma membranes revealed that ZIP14 is localized to the basolateral membrane of enterocytes. Studies utilizing 65 Zn administered by subcutaneous injection revealed greater zinc accumulation in the SI of Zip14 KO mice compared with WT mice. Isolation of endosomes confirmed the presence of ZIP14. Quantification of endosomal zinc concentration by FluoZin-3AM fluorescence demonstrated that zinc is trapped in endosomes of Zip14 KO mice. Intestinal permeability assessed both by plasma FITC-dextran following gavage and by serum endotoxin content was greater in Zip14 KO mice. Threonine phosphorylation of the tight junction protein occludin, which is necessary for tight junction assembly, was reduced in KO mice. Claudin 1 and 2, known to have an inverse relationship in regards to tight junction integrity, reflected impaired barrier function in KO jejunum. These data suggest involvement of ZIP14 in providing zinc for a regulatory role needed for maintenance of the intestinal barrier. In conclusion, ZIP14 is a basolaterally localized protein in enterocytes and is involved in endosomal trafficking of zinc and is necessary for proper maintenance of intestinal tight junctions. endotoxemia; zinc transporter; endosomes; intestinal permeability; mucosal defense THE GASTROINTESTINAL TRACT is responsible for both homeostatic control of zinc metabolism and zinc-dependent host barrier functions. Consequently, intestinal dysfunction as produced by inflammation influences zinc biology. Two families of metal ion transporters, comprised of a total of 24 individual members, the ZnT (SLC30A) and ZIP (SLC39A) proteins, are the major components of metabolic and functional pathways for zinc (16,17). These metabolic pathways act as homeostatic determinants of zinc absorption from the gastrointestinal tract and potentiate the release of endogenous zinc, particularly pancreatic secretions (16). Both Zip and Znt transporters are regulated at the transcriptional and posttranslational level.

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Section: Discussionmentioning

confidence: 99%

Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function

Guthrie

Aydemir

Troche

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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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] .…”

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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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“…Among them, PP2A is an effective tau phosphatase that dephosphorylates tau on Ser199, Ser202, Thr205, Ser396 and Ser404 [151][152][153], and restores the normal activity of tau. Inhibition of PP2A by okadaic acid, homocysteine, or zinc further increase tau phosphorylation levels and toxicities [154][155][156]. In vivo, PP2A activity can be inhibited by I2PP2A (inhibitor 2 of PP2A), which is phosphorylated at Ser9 and accumulated in the cytoplasm, resulting in increased PP2A inhibition and tau hyperphosphorylation in AD brains [157].…”

Section: Hyperphosphorylation and Tau Toxicitymentioning

confidence: 99%

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

Huang

Zhou

2015

Cell. Mol. Life Sci.

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tau, a microtubule-associated protein, directly binds with microtubules to dynamically regulate the organization of cellular cytoskeletons, and is especially abundant in neurons of the central nervous system. Under disease conditions such as Pick's disease, progressive supranuclear palsy, frontotemporal dementia, parkinsonism linked to chromosome 17 and Alzheimer's disease, tau proteins can self-assemble to paired helical filaments progressing to neurofibrillary tangles. In these diseases, collectively referred to as "tauopathies", alterations of diverse tau modifications including phosphorylation, metal ion binding, glycosylation, as well as structural changes of tau proteins have all been observed, indicating the complexity and variability of factors in the regulation of tau toxicity. Here, we review our current knowledge and hypotheses from relevant studies on tau toxicity, emphasizing the roles of phosphorylations, metal ions, folding and clearance control underlining tau etiology and their regulations. A summary of clinical efforts and associated findings of drug candidates under development is also presented. It is hoped that a more comprehensive understanding of tau regulation will provide us with a better blueprint of tau networking in neuronal cells and offer hints for the design of more efficient strategies to tackle tau-related diseases in the future.

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Zinc induces protein phosphatase 2A inactivation and tau hyperphosphorylation through Src dependent PP2A (tyrosine 307) phosphorylation

Cited by 109 publications

References 55 publications

Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function

Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function

Tau-induced neurodegeneration: mechanisms and targets

Behind the curtain of tauopathy: a show of multiple players orchestrating tau toxicity

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