Insight into cognitive decline from Zn 2+  dynamics through extracellular signaling of glutamate and glucocorticoids

Takeda, Atsüshi; Tamano, Hanuna

doi:10.1016/j.abb.2016.06.021

Cited by 22 publications

(11 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glucocorticoids also affect cognitive functions. It has been discussed how the increased levels of glucocorticoids under zinc deficiency alter brain functions associated with zinc signalling [159].…”

Section: Zinc and Cell Deathmentioning

confidence: 99%

The redox biology of redox-inert zinc ions

Maret

2019

Free Radical Biology and Medicine

180

124

View full text Add to dashboard Cite

Zinc(II) ions are redox-inert in biology. Yet, their interaction with sulfur of cysteine in cellular proteins can confer ligandcentered redox activity on zinc coordination sites, control protein functions, and generate signalling zinc ions as potent effectors of many cellular processes. The specificity and relative high affinity of binding sites for zinc allow regulation in redox biology, free radical biology, and the biology of reactive species. Understanding the role of zinc in these areas of biology requires an understanding of how cellular Zn2+ is homeostatically controlled and can serve as a regulatory ion in addition to Ca2+, albeit at much lower concentrations. A rather complex system of dozens of transporters and metallothioneins buffer the relatively high (hundreds of micromolar) total cellular zinc concentrations in such a way that the available zinc ion concentrations are only picomolar but can fluctuate in signalling. The proteins targeted by Zn2+ transients include enzymes controlling phosphorylation and redox signalling pathways. Networks of regulatory functions of zinc integrate gene expression and metabolic and signalling pathways at several hierarchical levels. They affect enzymatic catalysis, protein structure and protein-protein/biomolecular interactions and add to the already impressive number of catalytic and structural functions of zinc in an estimated three thousand human zinc proteins. The effects of zinc on redox biology have adduced evidence that zinc is an antioxidant. Without further qualifications, this notion is misleading and prevents a true understanding of the roles of zinc in biology. Its antioxidant-like effects are indirect and expressed only in certain conditions because a lack of zinc and too much zinc have pro-oxidant effects. Teasing apart these functions based on quantitative considerations of homeostatic control of cellular zinc is critical because opposite consequences are observed depending on the concentrations of zinc: pro-or anti-apoptotic, pro-or anti-inflammatory and cytoprotective or cytotoxic. The article provides a biochemical basis for the links between redox and zinc biology and discusses why zinc has pleiotropic functions. Perturbation of zinc metabolism is a consequence of conditions of redox stress. Zinc deficiency, either nutritional or conditioned, and cellular zinc overload cause oxidative stress. Thus, there is causation in the relationship between zinc metabolism and the many diseases associated with oxidative stress. Highlights• Redox-inert zinc ions regulate some aspects of redox biology and the biology or reactive species.• Control of cellular zinc homeostasis determines antioxidant-like or pro-oxidant effects.• Zinc deficiency and overload cause oxidative stress.• Disorders of zinc metabolism are a cause or consequence of diseases associated with oxidative stress.Abbreviations ER, endoplasmic reticulum; GCL, glutamate cysteine ligase; MT, metallothionein; MTF-1, metal regulatory element (MRE)-binding transcription factor-1; NOS, nitric oxide syntha...

show abstract

Section: Zinc and Cell Deathmentioning

confidence: 99%

The redox biology of redox-inert zinc ions

Maret

2019

Free Radical Biology and Medicine

180

124

View full text Add to dashboard Cite

show abstract

“…It is well-known that brain zinc homeostasis is strictly controlled to guarantee physiological function under healthy conditions. Vesicular zinc serves as a signal factor in a subclass of glutamatergic neurons, which is linked to glutamate signaling and cognitive activity [37,38]. Specially, vesicular zinc can inhibit glutamate release.…”

Section: Discussionmentioning

confidence: 99%

Disruption of zinc transporter ZnT3 transcriptional activity and synaptic vesicular zinc in the brain of Huntington’s disease transgenic mouse

Niu

Yang

et al. 2020

Cell Biosci

View full text Add to dashboard Cite

Background Huntington’s disease (HD) is a neurodegenerative disease that involves a complex combination of psychiatric, cognitive and motor impairments. Synaptic dysfunction has been implicated in HD pathogenesis. However, the mechanisms have not been clearly delineated. Synaptic vesicular zinc is closely linked to modulating synaptic transmission and maintaining cognitive ability. It is significant to assess zinc homeostasis for further revealing the pathogenesis of synaptic dysfunction and cognitive impairment in HD. Results Histochemical staining by autometallography indicated that synaptic vesicular zinc was decreased in the hippocampus, cortex and striatum of N171-82Q HD transgenic mice. Analyses by immunohistochemistry, Western blot and RT-PCR found that the expression of zinc transporter 3 (ZnT3) required for transport of zinc into synaptic vesicles was obviously reduced in these three brain regions of the HD mice aged from 14 to 20 weeks and BHK cells expressing mutant huntingtin. Significantly, dual-luciferase reporter gene and chromatin immunoprecipitation assays demonstrated that transcription factor Sp1 could activate ZnT3 transcription via its binding to the GC boxes in ZnT3 promoter. Moreover, mutant huntingtin was found to inhibit the binding of Sp1 to the promoter of ZnT3 and down-regulate ZnT3 expression, and the decline in ZnT3 expression could be ameliorated through overexpression of Sp1. Conclusions This is first study to reveal a significant loss of synaptic vesicular zinc and a decline in ZnT3 transcriptional activity in the HD transgenic mice. Our work sheds a novel mechanistic insight into pathogenesis of HD that mutant huntingtin down-regulates expression of ZnT3 through inhibiting binding of Sp1 to the promoter of ZnT3 gene, causing disruption of synaptic vesicular zinc homeostasis. Disrupted vesicular zinc ultimately leads to early synaptic dysfunction and cognitive deficits in HD. It is also suggested that maintaining normal synaptic vesicular zinc concentration is a potential therapeutic strategy for HD.

show abstract

“…It is well-known that brain zinc homeostasis is strictly controlled to guarantee physiological function under healthy conditions. Vesicular zinc serves as a signal factor in a subclass of glutamatergic neurons, which is linked to glutamate signaling and cognitive activity [63,64]. Specially, vesicular zinc can inhibit glutamate release.…”

Section: Discussionmentioning

confidence: 99%

Mutant huntingtin reduces vesicular zinc level by inhibiting the binding of Sp1 to ZnT3 promoter

Niu

Yang

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Synaptic dysfunction caused by mutant huntingtin greatly contributes to Huntington’s disease (HD) pathogenesis. HD patients show cognitive impairment as well as uncontrolled movements. Vesicular zinc is closely linked to modulating synaptic transmission and maintaining cognitive ability. However, whether does mutant huntingtin affect zinc homeostasis in the brain or not? This will be of great significance for further revealing the pathogenesis of HD. Methods N171-HD82Q transgenic mice and cultured BHK cells expressing N-terminal mutant huntingtin fragment containing 160 glutamines (160Q BHK cells) were used to investigate the effect of mutant huntingtin on zinc homeostasis and its molecular mechanisms. Results Herein, we have demonstrated that the density of synaptic vesicular zinc decreases in the cortex, striatum and hippocampus of N171-82Q mice. Given that vesicular zinc concentration depends on the abundance of zinc transporter 3 (ZnT3) on the membrane of synaptic vesicles, ZnT3 expression is detected in the brain of N171-82Q mice and 160Q BHK cells. Mutant huntingtin leads to a dramatical decrease in ZnT3 mRNA and protein levels in the three brain regions of these mice aged from 14 to 20 weeks. Significantly, Sp1 activates ZnT3 transcription via its binding to the GC boxes in ZnT3 promoter. Nevertheless, mutant huntingtin inhibits the binding of Sp1 to the promoter of ZnT3 gene and down-regulates ZnT3 expression. Furthermore, the overexpression of Sp1 ameliorates inhibition of ZnT3 gene transcription by mutant huntingtin. Conclusions Collectively, this first study to reveal a significant loss of synaptic vesicular zinc and ZnT3 expression caused by mutant huntingtin in the early stage of HD. Our findings have revealed the molecular mechanism underlying this change. Mutant huntingtin inhibits the binding of Sp1 to ZnT3 gene promoter to reduce ZnT3 expression. The imbalance of vesicular zinc homeostasis may be closely associated with synaptic dysfunction and cognitive deficits in HD. This work sheds novel mechanistic insights into the pathogenesis of HD and promises a potential therapeutic strategy for HD.

show abstract

Insight into cognitive decline from Zn 2+ dynamics through extracellular signaling of glutamate and glucocorticoids

Cited by 22 publications

References 120 publications

The redox biology of redox-inert zinc ions

The redox biology of redox-inert zinc ions

Disruption of zinc transporter ZnT3 transcriptional activity and synaptic vesicular zinc in the brain of Huntington’s disease transgenic mouse

Mutant huntingtin reduces vesicular zinc level by inhibiting the binding of Sp1 to ZnT3 promoter

Contact Info

Product

Resources

About