Developmental Expression of ZnT3 in Mouse Brain: Correlation between the Vesicular Zinc Transporter Protein and Chelatable Vesicular Zinc (CVZ) Cells. Glial and Neuronal CVZ Cells Interact

Valente, Tony; Auladell, Carme

doi:10.1006/mcne.2002.1159

Cited by 43 publications

(22 citation statements)

References 63 publications

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“…Recently, co-immunoprecipitation and Western blot analysis revealed that ZnT3 forms covalent homodimers mediated by intermolecular dityrosine bonds, which are induced by oxidative stress (22); these covalent dityrosine bonds were found to modulate subcellular localization and zinc transport activity of ZnT3 (22). Herein we showed that homodimers of ZnT3 localize at intracellular vesicles, consistent with its vesicular localization in the brain (45). The ability to assess and visualize ZnT3 homodimerization in situ using BiFC in live cells provides an advantage in examining the role of oxidative stress in ZnT3 homodimerization.…”

Section: Discussionsupporting

confidence: 69%

In Situ Dimerization of Multiple Wild Type and Mutant Zinc Transporters in Live Cells Using Bimolecular Fluorescence Complementation

Lasry

Golan

Berman

et al. 2014

Journal of Biological Chemistry

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Background: Zinc transporters (ZnTs) presumably form dimers, thereby modulating zinc transport activity. Results: Bimolecular fluorescence complementation (BiFC) revealed ZnT1-4, ZnT7 homodimers and ZnT5-ZnT6 heterodimers. Conclusion: BiFC pinpointed WT and mutant ZnT2 dimerization in live cells. Significance: BiFC provides the first in situ evidence for the subcellular localization of WT and mutant ZnT2 dimers in live cells, thereby establishing the molecular basis underlying zinc deficiency.

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Section: Discussionsupporting

confidence: 69%

In Situ Dimerization of Multiple Wild Type and Mutant Zinc Transporters in Live Cells Using Bimolecular Fluorescence Complementation

Lasry

Golan

Berman

et al. 2014

Journal of Biological Chemistry

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“…From these findings, we propose that Zn 2ϩ is needed to sustain synaptic health during aging through modulation of metabotropic and other postsynaptic targets. In the mouse brain, ZnT3 expression and the presence of synaptic vesicular Zn 2ϩ commence in late embryonic development and increase until weaning (Valente and Auladell, 2002). Here, we find that with aging hippocampal zinc and ZnT3 decline for uncertain reasons, possibly related to the need for energy to sustain zinc levels in the brain (Melov et al, 2007).…”

Section: Discussionmentioning

confidence: 69%

Cognitive Loss in Zinc Transporter-3 Knock-Out Mice: A Phenocopy for the Synaptic and Memory Deficits of Alzheimer's Disease?

Adlard¹,

Parncutt²,

Finkelstein³

et al. 2010

J. Neurosci.

347

291

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Zinc transporter-3 (ZnT3) protein controls synaptic vesicular Zn 2ϩ levels, which is predicted to regulate normal cognitive function. Surprisingly, previous studies found that 6-to 10-week-old ZnT3 knock-out (KO) mice did not show impairment in the Morris water maze. We hypothesized that older ZnT3 KO animals would display a cognitive phenotype. Here, we report that ZnT3 KO mice exhibit age-dependent deficits in learning and memory that are manifest at 6 months but not at 3 months of age. These deficits are associated with significant alterations in key hippocampal proteins involved in learning and memory, as assessed by Western blot. These include decreased levels of the presynaptic protein SNAP25 (Ϫ46%; p Ͻ 0.01); the postsynaptic protein PSD95 (Ϫ37%; p Ͻ 0.01); the glutamate receptors AMPAR (Ϫ34%; p Ͻ 0.01), NMDAR2a (Ϫ64%; p Ͻ 0.001), and NMDAR2b (Ϫ49%; p Ͻ 0.05); the surrogate marker of neurogenesis doublecortin (Ϫ31%; p Ͻ 0.001); and elements of the BDNF pathway, pro-BDNF (Ϫ30%; p Ͻ 0.05) and TrkB (Ϫ22%; p Ͻ 0.01). In addition, there is a concomitant decrease in neuronal spine density (Ϫ6%; p Ͻ 0.05). We also found that cortical ZnT3 levels fall with age in wild-type mice (Ϫ50%; p Ͻ 0.01) in healthy older humans (ages, 48 -91 years; r 2 ϭ 0.47; p ϭ 0.00019) and particularly in Alzheimer's disease (AD) (Ϫ36%; p Ͻ 0.0001). Thus, age-dependent loss of transsynaptic Zn 2ϩ movement leads to cognitive loss, and since extracellular ␤-amyloid is aggregated by and traps this pool of Zn 2ϩ , the genetic ablation of ZnT3 may represent a phenocopy for the synaptic and memory deficits of AD.

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“…Znt3 appears to be the membrane protein necessary for synaptic vesicle zinc transport since genetic deletion of Znt3 results in complete disappearance of synaptic vesicle zinc without altering the levels of the major proteinbound zinc pool (24). In the brain, expression of Znt3 is developmentally regulated (45). Other than this developmental modulation in expression, little information is available as to the mechanisms regulating Znt3 levels in the brain.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Decreases Zinc Transporter 3 Expression and Synaptic Vesicle Zinc Levels in Mouse Brain

Lee

Kim

Hong

et al. 2004

Journal of Biological Chemistry

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Previous studies suggest that female sex hormones modulate synaptic zinc levels, which may influence amyloid plaque formation and Alzheimer's disease progression. We examined the effects of ovariectomy and estrogen supplement on the levels of synaptic zinc and zinc transporter protein Znt3 in the brain. Ovariectomy was performed on 5-month-old mice, and 2 weeks later, pellets containing vehicle, low (0.18 mg/pellet), or high dose (0.72 mg) 17␤-estradiol were implanted. After 4 weeks, animals were decapitated, and blood and brain were collected for analysis. Blood analysis indicated that estrogen implants altered plasma estrogen levels in a dose-dependent manner. Analysis of brain tissue showed that ovariectomy raised hippocampal synaptic vesicle zinc levels, whereas estrogen replacement lowered these zinc levels. Western blots revealed that Znt3 levels in the brain were modulated in parallel with synaptic zinc levels, whereas no change was detected in the levels of Znt3 mRNA, as determined by Northern blot and reverse transcriptase-PCR analysis. However, mRNA levels of the ␦ subunit of adaptor protein complex (AP)-3, which modulates the level of Znt3 levels, were altered by estrogen depletion or replacement. These data demonstrate that estrogen alters the levels of Znt3 and synaptic vesicle zinc in female mice, probably through changing AP-3 ␦ expression. Since synaptic zinc may play a key role in neuronal death in acute brain injury as well as in plaque formation in Alzheimer's disease, and since estrogen may be beneficial in both conditions, our results may provide new insights into the effects of estrogen on the brain.

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Developmental Expression of ZnT3 in Mouse Brain: Correlation between the Vesicular Zinc Transporter Protein and Chelatable Vesicular Zinc (CVZ) Cells. Glial and Neuronal CVZ Cells Interact

Cited by 43 publications

References 63 publications

In Situ Dimerization of Multiple Wild Type and Mutant Zinc Transporters in Live Cells Using Bimolecular Fluorescence Complementation

In Situ Dimerization of Multiple Wild Type and Mutant Zinc Transporters in Live Cells Using Bimolecular Fluorescence Complementation

Cognitive Loss in Zinc Transporter-3 Knock-Out Mice: A Phenocopy for the Synaptic and Memory Deficits of Alzheimer's Disease?

Estrogen Decreases Zinc Transporter 3 Expression and Synaptic Vesicle Zinc Levels in Mouse Brain

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