Selective ferroptosis vulnerability due to familial Alzheimer's disease presenilin mutations

Mutations in presenilin 1 and 2 (PS1 and PS2) cause autosomal dominant familial Alzheimer's disease (FAD). Ferroptosis has been implicated as a mechanism of neurodegeneration in AD since neocortical iron burden predicts Alzheimer's disease (AD) progression. We found that loss of the presenilins dramatically sensitizes multiple cell types to ferroptosis, but not apoptosis. FAD causal mutations of presenilins similarly sensitizes cells to ferroptosis. The presenilins promote the expression of GPX4, the selenoprotein checkpoint enzyme that blocks ferroptosis by quenching the membrane propagation of lethal hydroperoxyl radicals. Presenilin gamma-secretase activity cleaves Notch-1 to signal LRP8 expression, which then controls GPX4 expression by regulating the supply of selenium into the cell since LRP8 is the uptake receptor for selenoprotein P. Selenium uptake is thus disrupted by presenilin FAD mutations, suppressing GPX4 expression. Therefore, presenilin mutations may promote neurodegeneration by derepressing ferroptosis, which has implications for disease-modifying therapeutics.Peer reviewe

The structural basis of bacterial manganese import

肺炎球菌が細胞内にマンガンイオンを取り込むしくみ --膜輸送体PsaBCの立体構造の解明--. 京都大学プレスリリース. 2021-09-15.Metal ions are essential for all forms of life. In prokaryotes, ATP-binding cassette (ABC) permeases serve as the primary import pathway for many micronutrients including the first-row transition metal manganese. However, the structural features of ionic metal transporting ABC permeases have remained undefined. Here, we present the crystal structure of the manganese transporter PsaBC from Streptococcus pneumoniae in an open-inward conformation. The type II transporter has a tightly closed transmembrane channel due to “extracellular gating” residues that prevent water permeation or ion reflux. Below these residues, the channel contains a hitherto unreported metal coordination site, which is essential for manganese translocation. Mutagenesis of the extracellular gate perturbs manganese uptake, while coordination site mutagenesis abolishes import. These structural features are highly conserved in metal-specific ABC transporters and are represented throughout the kingdoms of life. Collectively, our results define the structure of PsaBC and reveal the features required for divalent cation transport

Effects of heavy metal exposure during fertilisation and development on Galaxias maculates embryos and larvae

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Investigating the role of cua-1 in maintaining copper homeostasis within a long-lived, insulin-signalling, C. elegans mutants

© 2018 Dr. Katherine Elizabeth GanioAgeing is a complex process characterised by the accumulation of damage across the hierarchy of biological organisation (i.e. from molecules up to organs) and leads to the increased susceptibility to death or disease. Increased production or deregulation of reactive oxygen species (ROS) are in part, responsible for the pathological changes that occur throughout normal age and are observed in age-related diseases. Changes in biometals, specifically copper, play a key role in these pathologies because their crucial requirement for aerobic respiration leads to the production of significant amounts of ROS. The cellular and subcellular mechanisms by which homeostasis of copper is maintained throughout the ageing process and how these mechanisms may interact with one another as well as other cell signalling processes remains unclear. Single gene mutations in an evolutionarily conserved insulin signalling pathway were found to extend healthy lifespan in Caenorhabditis elegans (C. elegans). While this discovery has built upon our understanding of how genes interact within pathways that regulate the rate of ageing within a whole organism model much of the subcellular processes involved in delayed ageing remain unresolved. More recently, the activity of the C. elegans ortholog of the mammalian P-type copper-transporting ATPase, cua-1, was shown to be a requirement for daf-2 longevity suggesting a potential role of copper metabolism in delayed ageing. Quantitation of total copper levels by inductively coupled plasma mass spectrometry (ICP-MS) throughout daf-2 lifespan revealed these mutants have lower total copper levels across much of their lifespan compared to normal ageing populations. Decreased cua-1 activity in daf-2 mutants lead to a decreased in median lifespan and an overall decrease in total copper levels across lifespan to which both features could be restored to nearly physiological conditions through supplementation of sub-toxic levels of copper (II) salts. Further analysis using size-exclusion chromatography-inductively coupled plasma mass spectrometry (SEC-ICP-MS) of soluble native copper-binding proteins revealed an increase in copper associated to a specific low molecular weight protein. Using known metal binding affinities of the two C. elegans metallothionein (MTL) isoforms as well as two metallothionein deletion mutants (singly and in combination) it is suggested this peak is metallothionein. All together these results indicate a specific pathway for copper metabolism that facilitates delayed ageing within daf-2 mutants

Beyond the transect : an alternative microchemical imaging method for fine scale analysis of trace elements in fish otoliths during early life

Microchemical analysis of otolith (calcified 'ear stones' used for balance and orientation) of fishes is an important tool for studying their environmental history and management. However, the spatial resolution achieved is often too coarse to examine short-term events occurring in early life. Current methods rely on single points or transects across the otolith surface, which may provide a limited view of elemental distributions, a matter that has not previously been investigated. Imaging by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) permits microchemical analyses of short-term events in early life with high (97% was achieved using a multi-point non matrix-matched calibration of National Institute of Standards and Technology (NIST) 610 and 612 (trace elements in glass) using Longerich's calculation method against the matrix-matched standard FEBS-1 (powdered red snapper [Lutjanus campechanus] otolith). The spatial resolution achieved in the otolith corresponded to a time period of 2±1days during the larval phase, and 4±1days during the post-settlement juvenile phase. This method has the potential to improve interpretations of early life-history events at scales corresponding to specific events. While the images showed gradients in Sr and Ba across the larval settlement zone more clearly than single transects, the method proved sample homogeneity throughout the structure; demonstrating that 2D scanning has no significant advantage over line scans.10 page(s

Host subversion of bacterial metallophore usage drives copper intoxication

ABSTRACT Microorganisms can acquire metal ions in metal-limited environments using small molecules called metallophores. While metals and their importers are essential, metals can also be toxic, and metallophores have limited ability to discriminate between metals. The impact of metallophore-mediated non-cognate metal uptake on bacterial metal homeostasis and pathogenesis remains to be defined. The globally significant pathogen Staphylococcus aureus uses the Cnt system to secrete the metallophore staphylopine in zinc-limited host niches. Here, we show that staphylopine and the Cnt system facilitate bacterial copper uptake, potentiating the need for copper detoxification. During in vivo infection, staphylopine usage increased S. aureus susceptibility to host-mediated copper stress, indicating that the innate immune response can harness the antimicrobial potential of altered elemental abundances in host niches. Collectively, these observations show that while the broad-spectrum metal-chelating properties of metallophores can be advantageous, the host can exploit these properties to drive metal intoxication and mediate antibacterial control. IMPORTANCE During infection, bacteria must overcome the dual threats of metal starvation and intoxication. This work reveals that the zinc-withholding response of the host sensitizes S. aureus to copper intoxication. In response to zinc starvation, S. aureus utilizes the metallophore staphylopine. The current work revealed that the host can leverage the promiscuity of staphylopine to intoxicate S. aureus during infection. Significantly, staphylopine-like metallophores are produced by a wide range of pathogens, suggesting that this is a conserved weakness that the host can leverage to toxify invaders with copper. Moreover, it challenges the assumption that the broad-spectrum metal binding of metallophores is inherently beneficial to bacteria

Selective ferroptosis vulnerability due to familial Alzheimer's disease presenilin mutations

Mutations in presenilin 1 and 2 (PS1 and PS2) cause autosomal dominant familial Alzheimer's disease (FAD). Ferroptosis has been implicated as a mechanism of neurodegeneration in AD since neocortical iron burden predicts Alzheimer's disease (AD) progression. We found that loss of the presenilins dramatically sensitizes multiple cell types to ferroptosis, but not apoptosis. FAD causal mutations of presenilins similarly sensitizes cells to ferroptosis. The presenilins promote the expression of GPX4, the selenoprotein checkpoint enzyme that blocks ferroptosis by quenching the membrane propagation of lethal hydroperoxyl radicals. Presenilin gamma-secretase activity cleaves Notch-1 to signal LRP8 expression, which then controls GPX4 expression by regulating the supply of selenium into the cell since LRP8 is the uptake receptor for selenoprotein P. Selenium uptake is thus disrupted by presenilin FAD mutations, suppressing GPX4 expression. Therefore, presenilin mutations may promote neurodegeneration by derepressing ferroptosis, which has implications for disease-modifying therapeutics.Peer reviewe

Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL)

© 2017 - IOS Press and the authors. All rights reserved. Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer's disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete