Ferritin as an important player in neurodegeneration

doi:10.1016/j.parkreldis.2011.03.016

Parkinsonism & Related Disorders

Volume 17, Issue 6, July 2011, Pages 423-430

https://doi.org/10.1016/j.parkreldis.2011.03.016 Get rights and content

Abstract

Oxidative stress is considered one of the pathways leading to neuronal death in neurodegenerative disease. Many published studies aimed to assess the possible role of iron in this process but no consensus has been reached. On the other hand little is known about the role played by the main iron storage protein – ferritin. In this review we discuss the data obtained using several methods – Mössbauer spectroscopy, electron microscopy and ELISA – from human brain tissue both in controls and in four neurodegenerative disorders – Parkinson’s (PD) and Alzheimer’s disease, progressive supranuclear palsy and neuroferritinopathy. Iron may only cause oxidative stress injury when it is available as labile iron for Fenton reaction. This may be related to the decreased ability of ferritin to retain iron within the iron core of ferritin. This happens in PD and in neuroferritinopathy. In PD there is a decrease in the concentration of L ferritin, while in neuroferritinopathy there is a genetically induced mutation in L ferritin causing its loss of function. We discuss the importance of the ratio H/L ferritin and its changes in neurodegeneration.

Section snippets

Oxidative stress and the role of iron in neurodegeneration

For decades, oxidative stress has been considered an important factor in the process of neurodegeneration. This theory proposes that an excess of free radicals leads to the death of nerve cells. The imbalance may be caused either by an increased production of free radicals or by insufficient neutralization by scavengers [1]. The human brain seems to be particularly vulnerable to oxidative stress injury because of its high concentrations of lipids and unsaturated fatty acids, of the relatively

Structure and function of ferritin

Ferritins were first identified some 70 years ago, and since then have been well characterized. They are found in almost every living system, with a remarkable conservation of the structure and the capacity to oxidize and incorporate iron. The properties of ferritins in animals, plants and bacteria have been the subject of many reviews and of a recent full issue of Biochimica Biophysica Acta (1800, 8, 2010).

Ferritins are composed of 24 subunits, and form an almost spherical shell delimiting a

Iron and ferritin in normal human brain tissue

Pathologically neurodegenerative diseases, that may be caused by oxidative stress, (Alzheimer’s (AD), PD and atypical parkinsonisms), take place in defined areas of human brain. The hippocampal cortex (Hip) is the most affected brain region in the early phases of AD; PD involves the substantia nigra (SN) and in atypical parkinsonisms other basal ganglia (e.g. globus pallidus GP) are affected as well. Therefore most studies investigating the etiology of neurodegeneration have analyzed these

Neurodegeneration with brain iron accumulation

Neurodegeneration with brain iron accumulation (NBIA) is a group of progressive extrapyramidal and cognitive disorders, which include the previously named Hallervorden–Spatz syndrome, neuroferritinopathy and aceruloplasminemia. The original eponym for the disease acknowledged the work of German neuropathologists Julius Hallervorden and Hugo Spatz. The new term NBIA is now favored in light of the unethical activities of Hallervorden and Spatz before and during World War II.

NBIA are characterized

Conclusions

The possible role of ferritin in neurodegeneration is shown schematically in Fig. 1, and the results of our experimental studies are summarized in Table 4.

There are several pathways leading to neurodegeneration. One of these is oxidative stress injury mediated by Fenton chemistry. Ferritin may play an important role in this process, particularly when mutations or its deregulation lead to inability to maintain iron within ferritin shell. The iron that is not retained may start production of free

Acknowledgments

Andrzej Friedman, Dariusz Koziorowski and Jolanta Galazka-Friedman were partially supported by a grant from Polish Ministry of Science, grant # 2 R. 07. P.W

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Gastric mucosal injury is the initial stage of the occurrence and development of gastric diseases. Oxidative stress and ferroptosis caused by the imbalance of redox and iron dynamics in gastric mucosal epithelial cells are present throughout the occurrence and development of gastric mucosal injury. Therefore, the inhibition of oxidative stress and ferroptosis is a potential target for the treatment of the gastric mucosal injury. Xiaojianzhong decoction (XJZ), which consists of six Chinese herbal medicines and extracts, is used for the treatment of diseases related to gastrointestinal mucosal injury; however, its specific mechanism of action has yet to be clarified. In this study, we clarified the protective effect of XJZ on gastric mucosa and revealed its underlying mechanism. We established a gastric mucosal injury model using aspirin and administered XJZ. Furthermore, we systematically evaluated the mucosal injury and examined the expression of genes related to oxidative stress, ferroptosis, and inflammation. The study found that XJZ significantly counteracted aspirin-induced gastric mucosal injury and inhibited oxidative stress and ferroptosis in mice. Upon examining SQSTM1/p62(p62)/Kelch-like ECH-associated protein 1 (Keap1)/Nuclear Factor erythroid 2-Related Factor 2 (Nrf2), a well-known signaling pathway involved in the regulation of oxidative stress and ferroptosis, we found that its activation was significantly inhibited by aspirin treatment and that this signaling pathway was activated after XJZ intervention. Our study suggests that XJZ may inhibit aspirin induced oxidative stress and ferroptosis via the p62/Keap1/Nrf2 signaling pathway, thereby attenuating gastric mucosal injury.
Hippocampal proteomic analysis reveals activation of necroptosis and ferroptosis in a mouse model of chronic unpredictable mild stress-induced depression
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Neuronal loss has been identified in depression, but its mechanisms are not fully understood. Proteomic analyses provide a novel insight to explore the potential mechanisms of such pathological alterations. In this study, mice were treated with chronic unpredictable mild stress (CUMS) for 2 months to establish depression models. The hippocampus was analyzed for proteomic patterns by mass spectrometry followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Behavioral tests showed that mice receiving CUMS showed depression-like symptoms such as anhedonia in the sucrose preference test (SPT) and behavioral despair in the forced swimming test (FST). CUMS induced anxiety-like behaviors in the open field test (OFT), but did not impair spatial learning and memory ability in the Morris water maze (MWM) test. Out of 4046 quantified proteins, 47 differentially expressed proteins were obtained between the CUMS and control groups. These proteins were functionally enriched in a series of biological processes. Among the notably enriched pathways, necroptosis and ferroptosis were significantly activated. Western blot and biochemical assay analyses identified changes in receptor-interacting protein kinase 3 (RIP3), phosphorylated mixed lineage kinase domain-like protein (p-MLKL), ferritin light chain 1 (Ftl1) and lipid peroxidation that were related to necroptosis and ferroptosis. Further, we found reduced levels of alpha-crystallin B (Cryab) and brain-derived neurotrophic factor (BDNF), which were also associated with neuronal survival. Our study highlighted that necroptosis and ferroptosis were involved in depression and partially account for neuronal loss, thereby providing potentially novel targets for the treatment of depression.
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^☆: The review of this paper was entirely handled by the Co-Editor-in-Chief, Z.K. Wszolek.

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ReviewFerritin as an important player in neurodegeneration☆

Abstract

Section snippets

Oxidative stress and the role of iron in neurodegeneration

Structure and function of ferritin

Iron and ferritin in normal human brain tissue

Neurodegeneration with brain iron accumulation

Conclusions

Acknowledgments

Free Radic Biol Med

Biochim Biophys Acta

Biochim Biophys Acta

J Biol Chem

J Biol Chem

Biochim Biophys Acta

J Biol Chem

Neurobiol Dis

J Biol Chem

Free Radic Biol Med

J Biol Chem

J Biol Chem

Blood Cells Mol Dis

Int J Biochem Cell Biol

Blood

J Mol Biol

J Mol Biol

Blood

Biochim Biophys Acta

Blood

Parkinsonism Relat Disord

Neurobiol Dis

Best Pract Res Clin Heamatol

Parkinsonism Relat Disord

Biochim Biophys Acta

J Struct Biol

Mechanisms involved in the generation of free radicals

Pathol Biol

Neurodegenerative diseases and oxidative stress

Nat Rev Drug Discov

The iron redox and hydrolysis chemistry of the ferritins

Biochim Biophys Acta

Iron(II) and hydrogen peroxide detoxification by human H-chain ferritin. An EPR spin-trapping study

Biochemistry

A cytosolic iron chaperone that delivers iron to ferritin

Science

Ferritin. Uptake, storage, and release of iron

Met Ions Biol Syst

Ferritins: iron/oxygen biominerals in protein nanocages

J Biol Inorg Chem

“Opening” the ferritin pore for iron release by mutation of conserved amino acids at interhelix and loop sites

Biochemistry

Oxidative stress and cell death in cells expressing L-ferritin variants causing neuroferritinopathy

Neurobiol Dis

Ferritin iron uptake and release. Structure-function relationships

Biochem J

Neisseria meningitidis accelerates ferritin degradation in host epithelial cells to yield an essential iron source

Mol Microbiol

Release of iron from ferritin requires lysosomal activity

Am J Physiol, Cell Physiol

Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome

EMBO J

Specific iron chelators determine the route of ferritin degradation

Blood

Characterization of mitochondrial ferritin in Drosophila

Proc Natl Acad Sci USA

Evidence for the presence of ferritin in plant mitochondria

Eur J Biochem

Review
Ferritin as an important player in neurodegeneration☆