Zinc Signal in Brain Diseases Portbury, Stuart D; Adlard, Paul A
International journal of molecular sciences,
11/2017, Letnik:
18, Številka:
12
Journal Article
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The divalent cation zinc is an integral requirement for optimal cellular processes, whereby it contributes to the function of over 300 enzymes, regulates intracellular signal transduction, and ...contributes to efficient synaptic transmission in the central nervous system. Given the critical role of zinc in a breadth of cellular processes, its cellular distribution and local tissue level concentrations remain tightly regulated via a series of proteins, primarily including zinc transporter and zinc import proteins. A loss of function of these regulatory pathways, or dietary alterations that result in a change in zinc homeostasis in the brain, can all lead to a myriad of pathological conditions with both acute and chronic effects on function. This review aims to highlight the role of zinc signaling in the central nervous system, where it may precipitate or potentiate diverse issues such as age-related cognitive decline, depression, Alzheimer's disease or negative outcomes following brain injury.
Traumatic brain injury (TBI) consists of acute and long-term pathophysiological sequelae that ultimately lead to cognitive and motor function deficits, with age being a critical risk factor for ...poorer prognosis. TBI has been recently linked to the development of neurodegenerative diseases later in life including Alzheimer's disease, Parkinson's disease, chronic traumatic encephalopathy, and multiple sclerosis. The accumulation of iron in the brain has been documented in a number of neurodegenerative diseases, and also in normal aging, and can contribute to neurotoxicity through a variety of mechanisms including the production of free radicals leading to oxidative stress, excitotoxicity and by promoting inflammatory reactions. A growing body of evidence similarly supports a deleterious role of iron in the pathogenesis of TBI. Iron deposition in the injured brain can occur via hemorrhage/microhemorrhages (heme-bound iron) or independently as labile iron (non-heme bound), which is considered to be more damaging to the brain. This review focusses on the role of iron in potentiating neurodegeneration in TBI, with insight into the intersection with neurodegenerative conditions. An important implication of this work is the potential for therapeutic approaches that target iron to attenuate the neuropathology/phenotype related to TBI and to also reduce the associated risk of developing neurodegenerative disease.
Ceruloplasmin is a ferroxidase that interacts with ferroportin to export cellular iron, but is not expressed in neurons. We recently reported that the amyloid precursor protein (APP) is the analogous ...iron-exporting chaperone for neurons and other cells. The ferroxidase activity of APP has since been called into question. Using a triplex Fe2+ oxidation assay, we analyzed the activity of a soluble form of APP (sAPPα) within a buffer of physiological pH and anionic charge, and determined that iron oxidation originated from phosphate. Using various techniques such as flow-cytometry to measure surface presented proteins, we confirmed that endogenous APP is essential for ferroportin persistence on the neuronal surface. Therefore, despite lacking ferroxidase activity, APP still supports iron export from neurons.
Symptoms of Parkinson's disease arise due to neuronal loss in multiple brain regions, especially dopaminergic neurons in the substantia nigra pars compacta. Current therapies aim to restore dopamine ...levels in the brain, but while these provide symptomatic benefit, they do not prevent ongoing neurodegeneration. Preventing neuronal death is a major strategy for disease-modifying therapies; however, while many pathogenic factors have been identified, it is currently unknown how neurons die in the disease. Ferroptosis, a recently identified iron-dependent cell death pathway, involves several molecular events that have previously been implicated in PD. This review will discuss ferroptosis and other cell death pathways implicated in PD neurodegeneration, with a focus on the potential to therapeutically target these pathways to slow the progression of this disease.
•Cell death pathways potentially involved in Parkinson's disease are discussed.•Targeting cell death pathways for disease-modification in Parkinson's is discussed.•Research that implicates ferroptosis in Parkinsonian neurodegeneration is profiled.
Cellular senescence is characterised by the irreversible arrest of proliferation, a pro-inflammatory secretory phenotype and evasion of programmed cell death mechanisms. We report that senescence ...alters cellular iron acquisition and storage and also impedes iron-mediated cell death pathways. Senescent cells, regardless of stimuli (irradiation, replicative or oncogenic), accumulate vast amounts of intracellular iron (up to 30-fold) with concomitant changes in the levels of iron homeostasis proteins. For instance, ferritin (iron storage) levels provided a robust biomarker of cellular senescence, for associated iron accumulation and for resistance to iron-induced toxicity. Cellular senescence preceded iron accumulation and was not perturbed by sustained iron chelation (deferiprone). Iron accumulation in senescent cells was driven by impaired ferritinophagy, a lysosomal process that promotes ferritin degradation and ferroptosis. Lysosomal dysfunction in senescent cells was confirmed through several markers, including the build-up of microtubule-associated protein light chain 3 (LC3-II) in autophagosomes. Impaired ferritin degradation explains the iron accumulation phenotype of senescent cells, whereby iron is effectively trapped in ferritin creating a perceived cellular deficiency. Accordingly, senescent cells were highly resistant to ferroptosis. Promoting ferritin degradation by using the autophagy activator rapamycin averted the iron accumulation phenotype of senescent cells, preventing the increase of TfR1, ferritin and intracellular iron, but failed to re-sensitize these cells to ferroptosis. Finally, the enrichment of senescent cells in mouse ageing hepatic tissue was found to accompany iron accumulation, an elevation in ferritin and mirrored our observations using cultured senescent cells.
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•Altered iron homeostasis in senescent cells is driven by impaired ferritinophagy.•Impaired ferritinophagy causes functional cellular iron deficiency.•senescent cells are resistant to iron mediated cell death including ferroptosis.
Zinc transporter-3 (ZnT3) protein controls synaptic vesicular Zn(2+) 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 (-46%; p < 0.01); the postsynaptic protein PSD95 (-37%; p < 0.01); the glutamate receptors AMPAR (-34%; p < 0.01), NMDAR2a (-64%; p < 0.001), and NMDAR2b (-49%; p < 0.05); the surrogate marker of neurogenesis doublecortin (-31%; p < 0.001); and elements of the BDNF pathway, pro-BDNF (-30%; p < 0.05) and TrkB (-22%; p < 0.01). In addition, there is a concomitant decrease in neuronal spine density (-6%; p < 0.05). We also found that cortical ZnT3 levels fall with age in wild-type mice (-50%; p < 0.01) in healthy older humans (ages, 48-91 years; r(2) = 0.47; p = 0.00019) and particularly in Alzheimer's disease (AD) (-36%; p < 0.0001). Thus, age-dependent loss of transsynaptic Zn(2+) movement leads to cognitive loss, and since extracellular beta-amyloid is aggregated by and traps this pool of Zn(2+), the genetic ablation of ZnT3 may represent a phenocopy for the synaptic and memory deficits of AD.
Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased ...mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and beta-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Ass load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD.
Ceruloplasmin is an iron‐export ferroxidase that is abundant in plasma and also expressed in glia. We found a ∼80% loss of ceruloplasmin ferroxidase activity in the substantia nigra of idiopathic ...Parkinson disease (PD) cases, which could contribute to the pro‐oxidant iron accumulation that characterizes the pathology. Consistent with a role for ceruloplasmin in PD etiopathogenesis, ceruloplasmin knockout mice developed parkinsonism that was rescued by iron chelation. Additionally, peripheral infusion of ceruloplasmin attenuated neurodegeneration and nigral iron elevation in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model for PD. These findings show, in principle, that intravenous ceruloplasmin may have therapeutic potential in PD. Ann Neurol 2013;73:554–559
Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, ...suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-beta (Abeta) plaques in the frontal cortex (38%; p = 0.018), the cortex at the level of the hippocampus (53%; p = 0.0003), and the hippocampus (40%; p = 0.06). This was associated with decreased cortical Abeta1-40 (35%; p = 0.005) and Abeta1-42 (22%; p = 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP for alpha-C-terminal fragment (alpha-CTF), 54% and p = 0.04; for beta-CTF, 35% and p = 0.03. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant (p < 0.02) reductions in escape latencies over the first 3 (of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.
Traumatic brain Injury (TBI) is a significant cause of death and long-term disability for which there are currently no effective pharmacological treatment options. In this study then, we utilized a ...mouse model of TBI to assess the therapeutic potential of the stable disaccharide trehalose, which is known to protect against oxidative stress, increase levels of chaperone molecules and enhance autophagy. Furthermore, trehalose has demonstrated neuroprotective properties in numerous animal models and has been proposed as a potential treatment for neurodegeneration. As TBI (and associated neurodegenerative disorders) is complicated by a sudden and dramatic change in brain metal concentrations, including iron (Fe) and zinc (Zn), the collective accumulation and translocation of which has been hypothesized to contribute to the pathogenesis of TBI, then we also sought to determine whether trehalose modulated the metal dyshomeostasis associated with TBI. In this study three-month-old C57Bl/6 wildtype mice received a controlled cortical impact TBI, and were subsequently treated for one month with trehalose. During this time animals were assessed on multiple behavioral tasks prior to tissue collection. Results showed an overall significant improvement in the Morris water maze, Y-maze and open field behavioral tests in trehalose-treated mice when compared to controls. These functional benefits occurred in the absence of any change in lesion volume or any significant modulation of biometals, as assessed by laser ablation inductively coupled plasma mass spectrometry. Western blot analysis, however, revealed an upregulation of synaptophysin, doublecortin and brain derived neurotrophic factor protein in trehalose treated mice in the contralateral cortex. These results indicate that trehalose may be efficacious in improving functional outcomes following TBI by a previously undescribed mechanism of action that has relevance to multiple disorders of the central nervous system.
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