Ferrosenescence: The iron age of neurodegeneration?

Sfera, Adonis; Bullock, Kelsey; Price, Amy; Inderias, Luzmin; Osorio, Carolina

doi:10.1016/j.mad.2017.11.012

Cited by 67 publications

(51 citation statements)

References 229 publications

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“…Our analysis of human, macaque, and marmoset revealed higher expression of pathways that have been implicated in longevity and anti-inflammatory responses; more specifically, DNA repair pathways, negative regulation of ferroptosis, and apoptotic cell clearance. Many hallmarks of human neurodegeneration specifically involve an increased presence of double-strand DNA damage and senescent cells as well as accumulation of iron and peroxidation of polyunsaturated fatty acids in CNS cells (Fielder et al, 2017;Maynard et al, 2015;Sfera et al, 2018). These putative longevity pathways could shed some light on the molecular basis of homeostatic microglial brain maintenance in long-living animals such as humans.…”

Section: Discussionmentioning

confidence: 99%

Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program

Geirsdóttir

David

Keren‐Shaul

et al. 2019

Cell

333

191

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Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer's and Parkinson's disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans.

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Section: Discussionmentioning

confidence: 99%

Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program

Geirsdóttir

David

Keren‐Shaul

et al. 2019

Cell

333

191

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“…Iron is also necessary for mitochondrial function, synaptic plasticity, and cognitive function development. Excessive intracellular iron accelerates senescence by destroying DNA and blocking the genome repair system, and such a process was defined as the occurrence of ferritin aging (Sfera et al, 2018). When iron homeostasis in the body is out of balance, autophagy of ferritin (namely, ferritinophagy) mediated by nuclear receptor coactivator 4 (NCOA4) releases iron bounds to ferritin (Kruer, 2013;Dowdle et al, 2014;Mancias et al, 2014;Gao et al, 2016) or an abnormal increase in labile iron pools (LIP) through dysregulation of transferrin and transferrin receptors (iron from the extracellular environment) (Gao et al, 2016;Hou et al, 2016).…”

Section: The Iron Metabolism-related Pathway For Ferroptosis Regulationmentioning

confidence: 99%

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

2020

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“…Astrocytes have a high capacity to store iron and prevent iron overload in neurons (reviewed in [4,8,9]), in part dependent on the activation of the Nrf2 defense pathway [29,30]. Aging has been associated with iron retention in many cell types, and in neurons, promoting neurodegeneration by ferroptosis [128], which may partly be due to circadian dysregulation. As disruption of the circadian rhythm may be associated with inadequate activation of Nrf2 and dysregulation of astrocyte-neuron interactions, control of the circadian clock and sleep-wake cycles are particularly important for the normalization of brain functions and neuronal protection.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

Ishii

Warabi

Mann

2019

Free Radical Biology and Medicine

140

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Astrocyte-neuron interactions protect neurons from iron-mediated toxicity. As dopamine can be metabolized to reactive quinones, dopaminergic neurons are susceptible to oxidative damage and ferroptosis-like induced cell death. Detoxification enzymes are required to protect neurons. Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of redox sensitive transcription factor Nrf2 in astrocytes and metabolic cooperation between astrocytes and neurons. This article reviews the importance of BDNF and astrocyte-neuron interactions in the protection of neurons against oxidative damages in rodent brains. We previously proposed that BDNF activates Nrf2 via the truncated TrkB.T1 and p75 receptor complex in astrocytes. Stimulation by BDNF generates the signaling molecule ceramide, which activates PKCζ leading to induction of the CK2-Nrf2 signaling axis. As a cell clock regulates p75 expression, we suggested that BDNF effectively activates Nrf2 in astrocytes during the rest phase. In contrast, neurons express both TrkB.FL and TrkB.T1, and TrkB.FL tyrosine kinase activity inhibits p75-dependent ceramide generation and internalizes p75. Therefore, BDNF may not effectively activate Nrf2 in neurons. Notably, neurons only weakly activate detoxification and antioxidant enzymes/proteins via the Nrf2-ARE signaling axis. Thus, astrocytes may provide relevant transcripts and/or proteins to neurons via microparticles/exosomes increasing neuronal resistance to oxidative stress. Circadian increases in the levels of circulating glucocorticoids may further facilitate material transfer from astrocytes to neurons via the stimulation of pannexin 1 channels-P2X7R signaling pathway in astrocytes at the beginning of the active phase. Dysregulation of astrocyte-neuron interactions could therefore contribute to the pathogenesis of neurodegenerative diseases including Parkinson's disease.

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Ferrosenescence: The iron age of neurodegeneration?

Cited by 67 publications

References 229 publications

Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program

Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

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