Meta-analysis of the relationship between amyotrophic lateral sclerosis and susceptibility to serum ferritin level elevation

Hu, Xiaohui; Yang, Yan; Su, Junfeng; Yao, Changjiang

doi:10.17712/nsj.2016.2.20150482

Cited by 10 publications

(7 citation statements)

References 22 publications

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“…It has long been known that in the ALS iron homeostasis is disrupted; there is higher iron in the CSF and spinal cord of ALS patients [137]. While there are a large number of studies that demonstrate elevated levels of serum ferritin in ALS [137,138,139], there is not yet a consensus regarding whether serum ferritin is predictive [139,140,141] or unrelated [137,138] to disease progression and survival rates.…”

Section: Ferritin As a Disease Biomarkermentioning

confidence: 99%

Emerging and Dynamic Biomedical Uses of Ferritin

Chiou

Connor

2018

Pharmaceuticals

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Ferritin, a ubiquitously expressed protein, has classically been considered the main iron cellular storage molecule in the body. Owing to the ferroxidase activity of the H-subunit and the nucleation ability of the L-subunit, ferritin can store a large amount of iron within its mineral core. However, recent evidence has demonstrated a range of abilities of ferritin that extends well beyond the scope of iron storage. This review aims to discuss novel functions and biomedical uses of ferritin in the processes of iron delivery, delivery of biologics such as chemotherapies and contrast agents, and the utility of ferritin as a biomarker in a number of neurological diseases.

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Section: Ferritin As a Disease Biomarkermentioning

confidence: 99%

Emerging and Dynamic Biomedical Uses of Ferritin

Chiou

Connor

2018

Pharmaceuticals

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“…With regards to iron, Hozumi et al [44] found ALS patients have higher cerebrospinal fluid iron concentrations. In addition, a very recent meta-analysis including 6 case-control studies found an association between elevated serum ferritin levels and ALS [45]. Exposure to mercury may be linked to the aetiology of ALS [46, 47].…”

Section: Introductionmentioning

confidence: 99%

Spatial Assessment of the Association between Long-Term Exposure to Environmental Factors and the Occurrence of Amyotrophic Lateral Sclerosis in Catalonia, Spain: A Population-Based Nested Case-Control Study

et al. 2018

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Background: It is believed that an interaction between genetic and non-genetic factors may be involved in the development of amyotrophic lateral sclerosis (ALS). With the exception of exposure to agricultural chemicals like pesticides, evidence of an association between environmental risk factors and ALS is inconsistent. Our objective here was to investigate the association between long-term exposure to environmental factors and the occurrence of ALS in Catalonia, Spain, and to provide evidence that spatial clusters of ALS related to these environmental factors exist. Methods: We carried out a nested case-control study constructed from a retrospective population-based cohort, covering the entire region. Environmental variables were the explanatory variables of interest. We controlled for both observed and unobserved confounders. Results: We have found some spatial clusters of ALS. The results from the multivariate model suggest that these clusters could be related to some of the environmental variables, in particular agricultural chemicals. In addition, in high-risk clusters, besides corresponding to agricultural areas, key road infrastructures with a high density of traffic are also located. Conclusion: Our results indicate that some environmental factors, in particular those associated with exposure to pesticides and air pollutants as a result of urban traffic, could be associated with the occurrence of ALS.

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“…These observations could indicate that microglial Ft upregulation occurs in response to intracellular soluble iron accumulation in SALS spinal cords. A number of recent studies have suggested the relationship between elevated serum levels of Ft, as a candidate biomarker for SALS, and the severity of clinical features of patients with this disease . Thus, elevated serum Ft levels in SALS patients may reflect microglial Ft overexpression in the motor neuron system, although the outlet pathway of Ft from the CNS to the systemic circulation has not yet been clearly identified.…”

Section: Discussionmentioning

confidence: 99%

Soluble iron accumulation induces microglial glutamate release in the spinal cord of sporadic amyotrophic lateral sclerosis

et al. 2019

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Previous studies on sporadic amyotrophic lateral sclerosis (SALS) demonstrated iron accumulation in the spinal cord and increased glutamate concentration in the cerebrospinal fluid. To clarify the relationship between the two phenomena, we first performed quantitative and morphological analyses of substances related to iron and glutamate metabolism using spinal cords obtained at autopsy from 12 SALS patients and 12 age‐matched control subjects. Soluble iron content determined by the Ferrozine method as well as ferritin (Ft) and glutaminase C (GLS‐C) expression levels on Western blots were significantly higher in the SALS group than in the control group, while ferroportin (FPN) levels on Western blots were significantly reduced in the SALS group as compared to the control group. There was no significant difference in aconitase 1 (ACO1) and tumor necrosis factor‐alpha (TNFα)‐converting enzyme (TACE) levels on Western blots between the two groups. Immunohistochemically, Ft, ACO1, TACE, TNFα, and GLS‐C were proven to be selectively expressed in microglia. Immunoreactivities for FPN and hepcidin were localized in neuronal and glial cells. Based on these observations, it is predicted that soluble iron may stimulate microglial glutamate release. To address this issue, cell culture experiments were carried out on a microglial cell line (BV‐2). Treatment of BV‐2 cells with ferric ammonium citrate (FAC) brought about significant increases in intracellular soluble iron and Ft expression levels and conditioned medium glutamate and TNFα concentrations. Glutamate concentration was also significantly increased in conditioned media of TNFα‐treated BV‐2 cells. While the FAC‐driven increases in glutamate and TNFα release were completely canceled by pretreatment with ACO1 and TACE inhibitors, respectively, the TNFα‐driven increase in glutamate release was completely canceled by GLS‐C inhibitor pretreatment. Moreover, treatment of BV‐2 cells with hepcidin resulted in a significant reduction in FPN expression levels on Western blots of the intracellular total protein extracts. The present results provide in vivo and in vitro evidence that microglial glutamate release in SALS spinal cords is enhanced by intracellular soluble iron accumulation‐induced activation of ACO1 and TACE and by increased extracellular TNFα‐stimulated GLS‐C upregulation, and suggest a positive feedback mechanism to maintain increased intracellular soluble iron levels, involving TNFα, hepcidin, and FPN.

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Meta-analysis of the relationship between amyotrophic lateral sclerosis and susceptibility to serum ferritin level elevation

Cited by 10 publications

References 22 publications

Emerging and Dynamic Biomedical Uses of Ferritin

Emerging and Dynamic Biomedical Uses of Ferritin

Spatial Assessment of the Association between Long-Term Exposure to Environmental Factors and the Occurrence of Amyotrophic Lateral Sclerosis in Catalonia, Spain: A Population-Based Nested Case-Control Study

Soluble iron accumulation induces microglial glutamate release in the spinal cord of sporadic amyotrophic lateral sclerosis

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