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Iron accumulation in whole brain of FVB mutated mice. A MRI brain examination of 18 and 22month-old controls and transgenic FVB mice. Left panel: RARE T2 (upper row) and SWI (lower row) coronal images are shown. Areas of brain iron accumulation are detected in vivo as multiple small dark hypointense areas. Right panel: the brain from the same animals were analyzed ex vivo, Fast Spin Echo T2 (upper row) and SWI (lower row) images confirm the results obtained in vivo and show the presence of iron accumulation at the level of the hippocampus, brain cortex and basal ganglia. B In vivo T2 relaxation times of WT- and Tg-FVB mice at 18 and 22months of age measured on T2 maps. These measurements revealed a significant reduction of the T2 decay in the brains of Tg mice with respect to the control, in particular in striatum, hippocampus, cerebellum and pons, highly suggestive of iron accumulation.
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Neuroferritinopathy is a rare genetic disease with a dominant autosomal transmission caused by mutations of the ferritin light chain gene (FTL). It belongs to Neurodegeneration with Brain Iron Accumulation, a group of disorders where iron dysregulation is tightly associated with neurodegeneration. We studied the 498–499InsTC mutation which causes t...
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Brain iron accumulation has been found to accelerate disease progression in amyloid-β(Aβ) positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological...
Citations
... Along these lines, lipofuscin accumulation decreases the ability of cells to adapt to amino acid starvation [32] and increases their susceptibility to oxidative stress [33]. Increases in the dietary intake of metal cations such as Fe 2+ , which plays a key role in the formation of lipofuscin, augments lipofuscin accumulation [34][35][36] and speeds up aging [37]. Manganese acts similarly [38]. ...
Lipofuscin is indigestible garbage that accumulates in the autophagic vesicles and cytosol of post-mitotic cells with age. Drs. Brunk and Terman postulated that lipofuscin accumulation is the main or at least a major driving factor in aging. They even posited that the evolution of memory is the reason why we get lipofuscin at all, as stable synaptic connections must be maintained over time, meaning that the somas of neurons must also remain in the same locale. In other words, they cannot dilute out their garbage over time through cell division. Mechanistically, their position certainly makes sense given that rendering a large percentage of a post-mitotic cell’s lysosomes useless must almost certainly negatively affect that cell and the surrounding microenvironment. Here, I explore the possibility that the accumulation of lipofuscin may to some extent exacerbate every other kind of age-related damage. I do not think that lipofuscin removal will reverse/prevent all forms of aging, just the major component facing us currently. In this piece, I will review what is known about lipofuscin accumulation from evolutionary and mechanistic standpoints and discuss a method of removing it from single cells in vitro.
... This subunit forms complexes with the H-ferritin subunit to form the heteropolymer ferritin [92]. The incorporation of the mutated subunit in ferritin heteropolymers results in a cytosolic increase in free redox-active iron due to the reduced ability of mutated ferritin to keep iron safely stored in its cavity [93][94][95][96][97]. NF patients show pathological iron deposition in different brain regions, especially in the globus pallidus [91,[98][99][100]]. ...
... Ultrastructural analysis of brains from NF transgenic mice confirmed the presence of iron-ferritin body complexes accompanied by signs of oxidative damage and revealed the impairment of the lysosomal compartment with the formation of lipofuscin. Lipofuscin, typical aging marker, is a pigment granule containing lipid residues of the lysosomal digestion and metal [94]. This evidence can explain the etiopathogenesis of human neuroferritinopathy [95]; moreover, new additional findings were obtained studying NF fibroblasts and induced pluripotent (iPS)derived NPCs and neurons [104,105]. ...
Iron is an essential element for the development and functionality of the brain, and anomalies in its distribution and concentration in brain tissue have been found to be associated with the most frequent neurodegenerative diseases. When magnetic resonance techniques allowed iron quantification in vivo, it was confirmed that the alteration of brain iron homeostasis is a common feature of many neurodegenerative diseases. However, whether iron is the main actor in the neurodegenerative process, or its alteration is a consequence of the degenerative process is still an open question. Because the different iron-related pathogenic mechanisms are specific for distinctive diseases, identifying the molecular mechanisms common to the various pathologies could represent a way to clarify this complex topic. Indeed, both iron overload and iron deficiency have profound consequences on cellular functioning, and both contribute to neuronal death processes in different manners, such as promoting oxidative damage, a loss of membrane integrity, a loss of proteostasis, and mitochondrial dysfunction. In this review, with the attempt to elucidate the consequences of iron dyshomeostasis for brain health, we summarize the main pathological molecular mechanisms that couple iron and neuronal death.
... Sen et al. [21] found that welders with manganese accumulation in the olfactory bulb showed deficits in fine motor skills. Previous studies using transgenic mice found that mice with iron overload in the olfactory bulb also had reduced activity and motor coordination [22] as well as compromised balance [23]. ...
... The aim of our study was to examine the relationship between mobility and trace element disruption in the olfactory bulb in male and female B6J and D2J mice fed a HFD. We hypothesized that there would be an inverse relationship between mobility and iron and manganese concentration in the olfactory bulb for male B6J mice fed a HFD based on our prior studies [27,28] and on reports in humans and animals that show a potential connection between elevated olfactory bulb metals and compromised mobility [20][21][22][23]. ...
... Combining our previous work [27,28] with our current study, we noticed that male B6J mice fed a HFD had a pattern of increased olfactory bulb iron, reduced velocity, and reduced TDT in the open field test. This is consistent with other studies [42] that found transgenic mice with iron overload in the olfactory bulb to have reduced activity, motor coordination [22], and balance [23]. Similar patterns showing iron overload in the brain coinciding with movement disorders have been observed in humans. ...
The dysregulation of trace elements in the brain, which can be caused by genetic or environmental factors, has been associated with disease and compromised mobility. Research regarding trace elements and motor function has focused mainly on the basal ganglia, but few studies have examined the olfactory bulb in this context. Diets high in fat have been shown to have consequences of dysregulated iron and manganese in the brain and disrupted motor activity. The aim of our study was to examine the relationship between mobility and trace element disruption in the olfactory bulb in male and female C57BL/6J and DBA/2J mice fed a high-fat diet. Mobility was significantly reduced in male C57BL/6Js, but the correlation between iron and manganese in the olfactory bulb with velocity, distance travelled, and habituation was not statistically significant. However, there appears to be an overall pattern of a high-fat diet having a statistically significant impact individually on elevated iron and manganese in the olfactory bulb, reduced velocity, reduced distance travelled, and reduced habituation mainly in the male C57BL/6J strain. We found similar trends within the scientific literature to suggest that dysregulated trace element status in the olfactory bulb may be related to motor function in both humans and animals and that males may be more susceptible to the negative outcomes. Our findings contribute new information regarding the impact of diet on the brain, behavior, and potential connection between trace element dysregulation in the olfactory bulb with mobility.
... Along these lines, lipofuscin accumulation decreases the ability of cells to adapt to amino acid starvation [32] and increases their susceptibility to oxidative stress [33]. Increases in the dietary intake of metal cations such as Fe 2+ , which plays a key role in the formation of lipofuscin, augments lipofuscin accumulation [34][35][36] and speeds up aging [37]. Manganese acts similarly [38]. ...
Lipofuscin is indigestible garbage that accumulates in the autophagic vesicles and cytosol of post-mitotic cells with age. Drs. Brunk and Terman postulated that lipofuscin accumulation is the main or at least a major driving factor in aging. They even posited that the evolution of memory is the reason why we get lipofuscin at all, as stable synaptic connections must be maintained over time, meaning that the somas of neurons must also remain in the same locale. In other words, they cannot dilute out their garbage over time through cell division. Mechanistically, their position certainly makes sense given that rendering a large percentage of a post-mitotic cell’s lysosomes useless must almost certainly negatively affect that cell and the surrounding microenvironment. Here, I explore the possibility that the accumulation of lipofuscin may to some extent exacerbate every other kind of age-related damage. I do not think that lipofuscin removal will reverse/prevent all forms of aging, just the major component facing us currently. In this piece, I will review what is known about lipofuscin accumulation from evolutionary and mechanistic standpoints and discuss a method of removing it from single cells in vitro.
... The FTL gene, encoding the ferritin light chain, is one of the few currently established NBIA genes known to be directly involved in iron homeostasis. [10][11][12][13][14][15] Recent studies suggest that multiple NBIA disorders are mechanistically linked to a mitochondrial acyl carrier protein, 16 but overall the molecular mechanisms leading to neurodegeneration in those genetic disorders remain incompletely understood. ...
Ferritin, the iron storage protein, is composed of light and heavy chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole exome sequencing, with a recurrent variant (p.Phe171*) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminus variants in FTH1 truncate ferritin's E-helix, altering the four-fold symmetric pores of the heteropolymer and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knock-down of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder.
... In our study, mutations in three genes (CP, FTL, and COQ2) have been related to the regulation of ferroptosis (count=3 (8.6%), log10(q)=−1.607). CP and FTL maintain iron homeostasis in neurons via oxidizing ferrous iron and regulating iron transportation,respectively [45,46]. Although COQ2 is not directly associated with iron metabolism, its products regulate the expression of CoQ10, which is mediated by ferroptosis suppressor protein 1 (FSP1) and suppresses the ferroptosis [47]. ...
Brain iron accumulation disorders (BIADs) are a group of diseases characterized by iron overload in deep gray matter nuclei, which is a common feature of neurodegenerative diseases. Although genetic factors have been reported to be one of the etiologies, much more details about the genetic background and molecular mechanism of BIADs remain unclear. This study aimed to illustrate the genetic characteristics of BIADs and clarify their molecular mechanisms. A total of 84 patients with BIADs were recruited from April 2018 to October 2022 at Xuanwu Hospital. Clinical characteristics including family history, consanguineous marriage history, and age at onset (AAO) were collected and assessed by two senior neurologists. Neuroimaging data were conducted for all the patients, including cranial magnetic resonance imaging (MRI) and susceptibility-weighted imaging (SWI). Whole-exome sequencing (WES) and capillary electrophoresis for detecting sequence mutation and trinucleotide repeat expansion, respectively, were conducted on all patients and part of their parents (whose samples were available). Variant pathogenicity was assessed according to the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP). The NBIA and NBIA-like genes with mutations were included for bioinformatic analysis, using Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genome (KEGG). GO annotation and KEGG pathway analysis were performed on Metascape platform. In the 84 patients, 30 (35.7%) were found to carry mutations, among which 20 carried non-dynamic mutations (missense, stop-gained, frameshift, inframe, and exonic deletion) and 10 carried repeat expansion mutations. Compared with sporadic cases, familial cases had more genetic variants (non-dynamic mutation: P=0.025, dynamic mutation: P=0.003). AAO was 27.85±10.42 years in cases with non-dynamic mutations, which was significantly younger than those without mutations (43.13±17.17, t=3.724, P<0.001) and those with repeated expansions (45.40±8.90, t=4.550, P<0.001). Bioinformatic analysis suggested that genes in lipid metabolism, autophagy, mitochondria regulation, and ferroptosis pathways are more likely to be involved in the pathogenesis of BIADs. This study broadens the genetic spectrum of BIADs and has important implications in genetic counselling and clinical diagnosis. Patients diagnosed as BIADs with early AAO and family history are more likely to carry mutations. Bioinformatic analysis provides new insights into the molecular pathogenesis of BIADs, which may shed lights on the therapeutic strategy for neurodegenerative diseases.
... Furthermore, we explored the mechanism by which fatostatin regulates ferroptosis in GBM cells by detecting the expression of ACSL4, SLC7A11, FTL, and GPX4, which are the core regulatory proteins of lipid oxidation and iron metabolism [21][22][23]. Our results revealed that only the expression of GPX4 was negatively altered with fatostatin treatment, while other molecules showed no significant change (Fig. 4F, G and Supplementary Fig. 2D). ...
Glioblastoma multiforme (GBM) is the most common and fatal primary malignant central nervous system tumor in adults. Although there are multiple treatments, the median survival of GBM patients is unsatisfactory, which has prompted us to continuously investigate new therapeutic strategies, including new drugs and drug delivery approaches. Ferroptosis, a kind of regulated cell death (RCD), has been shown to be dysregulated in various tumors, including GBM. Fatostatin, a specific inhibitor of sterol regulatory element binding proteins (SREBPs), is involved in lipid and cholesterol synthesis and has antitumor effects in a variety of tumors. However, the effect of fatostatin has not been explored in the field of ferroptosis or GBM. In our study, through transcriptome sequencing, in vivo experiments, and in vitro experiments, we found that fatostatin induces ferroptosis by inhibiting the AKT/mTORC1/GPX4 signaling pathway in glioblastoma. In addition, fatostatin inhibits cell proliferation and the EMT process through the AKT/mTORC1 signaling pathway. We also designed a p28-functionalized PLGA nanoparticle loaded with fatostatin, which could better cross the blood-brain barrier (BBB) and be targeted to GBM. Our research identified the unprecedented effects of fatostatin in GBM and presented a novel drug-targeted delivery vehicle capable of penetrating the BBB in GBM.
... It has been reported that the loss of FTH results in oxidative stress and impairs cortical iron homeostasis in mice [28,29]. Mutations in FTL contribute to brain iron dysregulation, early morphological signs of neurodegeneration, and motor coordination deficits [30]. Therefore, ferritin plays an important role in the stability of iron levels and in neuroprotection. ...
Ferroptosis and iron-related redox imbalance aggravate traumatic brain injury (TBI) outcomes. NRF2 is the predominant transcription factor regulating oxidative stress and neuroinflammation in TBI, but its role in iron-induced post-TBI damage is unclear. We investigated ferroptotic neuronal damage in the injured cortex and observed neurological deficits post-TBI. These were ameliorated by the iron chelator deferoxamine (DFO) in wild-type mice. In Nrf2-knockout (Nrf2−/−) mice, more sever ferroptosis and neurological deficits were detected. Dimethyl fumarate (DMF)-mediated NRF2 activation alleviated neural dysfunction in TBI mice, partly due to TBI-induced ferroptosis mitigation. Additionally, FTH-FTL and FSP1 protein levels, associated with iron metabolism and the ferroptotic redox balance, were highly NRF2-dependent post-TBI. Thus, NRF2 is neuroprotective against TBI-induced ferroptosis through both the xCT-GPX4- and FTH-FTL-determined free iron level and the FSP1-regulated redox status. This yields insights into the neuroprotective role of NRF2 in TBI-induced neuronal damage and its potential use in TBI treatment.
... To determine the mechanism of RND1 in regulating ferroptosis in GBM cells, the expression of several core regulatory proteins of iron metabolism and lipid oxidation were evaluated, including SLC7A11, GPX4, ACSL4, and FTL [6,[19][20][21], when RND1 was overexpressed or knocked down ( Fig. 3A and Additional file 4: Fig. S4A, B). It was observed that SLC7A11, a component of system x c − that maintains the stability of lipid oxidation in cells, was negatively regulated by RND1 in vitro ( Fig. 3 and Additional file 4: Fig. S4). ...
Background
Ferroptosis is an iron dependent cell death closely associated with p53 signaling pathway and is aberrantly regulated in glioblastoma (GBM), yet the underlying mechanism needs more exploration. Identifying new factors which regulate p53 and ferroptosis in GBM is essential for treatment.
Methods
Glioma cell growth was evaluated by cell viability assays and colony formation assays. Lipid reactive oxygen species (ROS) assays, lipid peroxidation assays, glutathione assays, and transmission electron microscopy were used to assess the degree of cellular lipid peroxidation of GBM. The mechanisms of RND1 in regulation of p53 signaling were analyzed by RT-PCR, western blot, immunostaining, co-immunoprecipitation, ubiquitination assays and luciferase reporter assays. The GBM‐xenografted animal model was constructed and the tumor was captured by an In Vivo Imaging System (IVIS).
Results
From the The Cancer Genome Atlas (TCGA) database, we summarized that Rho family GTPase 1 (RND1) expression was downregulated in GBM and predicted a better prognosis of patients with GBM. We observed that RND1 influenced the glioma cell growth in a ferroptosis-dependent manner when GBM cell lines U87 and A172 were treated with Ferrostatin-1 or Erastin. Mechanistically, we found that RND1 interacted with p53 and led to the de-ubiquitination of p53 protein. Furthermore, the overexpression of RND1 promoted the activity of p53-SLC7A11 signaling pathway, therefore inducing the lipid peroxidation and ferroptosis of GBM.
Conclusions
We found that RND1, a novel controller of p53 protein and a positive regulator of p53 signaling pathway, enhanced the ferroptosis in GBM. This study may shed light on the understanding of ferroptosis in GBM cells and provide new therapeutic ideas for GBM.
... Transgenic mice expressing the ferritin variant c.497_498dupTC were developed in two distinct laboratories using different approaches (promoter and mouse strains). Both models [80,81] showed the formation of iron and ferritin bodies, similar to those detected in patient brains [50]. However, some differences have been detected regarding the localization of these bodies in brain tissues. ...
... Vidal and collaborators observed aggregates located in the cytosol and in the nucleus of neuronal cells in the CNS and in other organs [81]. On the other hand, Maccarinelli et al. [80], who developed transgenic mouse models for the same mutation in two different strains (FVB and C57Bl/6), never detected the presence of aggregates in the nucleus. Nevertheless, they revealed, by ultrastructural analyses, an accumulation of lipofuscin granules associated with iron deposits surrounding the nucleus [80]. ...
... On the other hand, Maccarinelli et al. [80], who developed transgenic mouse models for the same mutation in two different strains (FVB and C57Bl/6), never detected the presence of aggregates in the nucleus. Nevertheless, they revealed, by ultrastructural analyses, an accumulation of lipofuscin granules associated with iron deposits surrounding the nucleus [80]. These lipofuscin granules were particularly enriched in the cerebellum and striatum of the transgenic mice, and they increased in number during aging [80]. ...
Neuroferritinopathy is a rare autosomal dominant inherited movement disorder caused by alteration of the L-ferritin gene that results in the production of a ferritin molecule that is unable to properly manage iron, leading to the presence of free redox-active iron in the cytosol. This form of iron has detrimental effects on cells, particularly severe for neuronal cells, which are highly sensitive to oxidative stress. Although very rare, the disorder is notable for two reasons. First, neuroferritinopathy displays features also found in a larger group of disorders named Neurodegeneration with Brain Iron Accumulation (NBIA), such as iron deposition in the basal ganglia and extrapyramidal symptoms; thus, the elucidation of its pathogenic mechanism may contribute to clarifying the incompletely understood aspects of NBIA. Second, neuroferritinopathy shows the characteristic signs of an accelerated process of aging; thus, it can be considered an interesting model to study the progress of aging. Here, we will review the clinical and neurological features of neuroferritinopathy and summarize biochemical studies and data from cellular and animal models to propose a pathogenic mechanism of the disorder.
