H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Nandar, Wint; Neely, Elizabeth B.; Simmons, Zachary; Connor, James R.

doi:10.1016/j.bbadis.2014.09.016

Cited by 27 publications

(25 citation statements)

References 74 publications

(120 reference statements)

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“…Conversely, in patients with SOD1 mutations the presence of a G allele was found to be significantly associated with a longer survival. This finding is in contrast with the reported shorter survival in the double transgenic mouse line (SOD1/H67D) (Nandar et al, 2014), highlighting the possibility that genetic interactions in mice compared with humans are biologically different. However, because of the small number of patients carrying a SOD1 mutation in this series, our finding should be considered with caution, because of the possibility of a type 1 error.…”

Section: Discussioncontrasting

confidence: 90%

“…The authors also found that the presence of the G allele was associated with a reduction of SOD1 activity in the muscle and that SOD1 protein expression was negatively associated with total disease duration in ALS patients. In a subsequent article, the same group reported that a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homolog of human H63D) and SOD1 (G93A) mutations have a shorter survival and an accelerated disease progression (Nandar et al, 2014); they therefore concluded that when HFE is combined with a mutation in an ALS gene the disease duration could be negatively impacted. The authors suggested that H63D HFE polymorphism can modify ALS pathophysiology via pathways involving oxidative stress, gliosis, and disruption of cellular functions.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression in the ALS SOD1 transgenic mouse (Nandar et al, 2014). Conversely, in a small study on 35 ALS patients, it has been reported that patients carrying the p.H63D polymorphism of the HFE gene had a significantly longer survival than those with the wild-type gene (Su et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

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HFE p.H63D polymorphism does not influence ALS phenotype and survival

Chiò

Mora

Sabatelli³

et al. 2015

Neurobiology of Aging

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It has been recently reported that the p.His63Asp polymorphism of the HFE gene accelerates disease progression both in the SOD1 transgenic mouse and in amyotrophic lateral sclerosis (ALS) patients. We have evaluated the effect of HFE p.His63Asp polymorphism on the phenotype in 1351 Italian ALS patients (232 of Sardinian ancestry). Patients were genotyped for the HFE p.His63Asp polymorphism (CC, GC, and GG). All patients were also assessed for C9ORF72, TARDBP, SOD1, and FUS mutations. Of the 1351 ALS patients, 363 (29.2%) were heterozygous (GC) for the p.His63Asp polymorphism and 30 (2.2%) were homozygous for the minor allele (GG). Patients with CC, GC, and GG polymorphisms did not significantly differ by age at onset, site of onset of symptoms, and survival; however, in SOD1 patients with CG or GG polymorphism had a significantly longer survival than those with a CC polymorphism. Differently from what observed in the mouse model of ALS, the HFE p.His63Asp polymorphism has no effect on ALS phenotype in this large series of Italian ALS patients.

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Section: Discussioncontrasting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HFE p.H63D polymorphism does not influence ALS phenotype and survival

Chiò

Mora

Sabatelli³

et al. 2015

Neurobiology of Aging

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“…Human brain tissue (IRB# 40726) was obtained and sectioned in 5‐micron slices. Immunohistochemistry and immunofluorescence was performed as previously described (Connor et al, ; Nandar et al, ). Briefly, slides were deparaffinized and hydrated, performing antigen retrieval with 10mM citrate buffer, pH 6.0.…”

Section: Methodsmentioning

confidence: 99%

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Chiou

Lucassen

Sather

et al. 2018

Glia

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Deficiency of trophic factors relating to the survival of oligodendrocytes, combined with direct interactions with the immune system, are favored paradigms that are increasingly implicated in demyelinating diseases of the central nervous system. We and others have previously shown that Sema4A and H-ferritin interact through the T-cell immunoglobulin and mucin domain (Tim-2) receptor in mice. H-ferritin has been identified as the iron delivery protein for oligodendrocytes, whereas Sema4A causes a direct cytotoxic effect. However, the expression of Tim-2 has not been detected in humans. Here, we demonstrate that, similar to rodents, human oligodendrocytes undergo apoptosis when exposed to Sema4A and take up H-ferritin for meeting iron requirements and that these functions are mediated via the Tim-1 receptor. Moreover, we also demonstrate the ability of H-ferritin to block Sema4A-mediated cytotoxicity. Furthermore, we show in a series of pilot studies that Sema4A is detectable in the CSF of multiple sclerosis patients and HIV-seropositive persons and can induce oligodendrocyte cell death. Together, these results identify a novel iron uptake mechanism for human oligodendrocytes and a connection between oligodendrocytes and the immune system.

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“…The H63D mutation and its interaction with other HFE mutations and neurodegenerative disorders remain under investigation (Nandar et al 2014; Ali-Rahmani et al 2014b; Xia et al 2015; Mariani et al 2013; Pulliam et al 2003; Gazzina et al 2015). The MRI data presented here demonstrate that there is an HFE genome related reduction in transverse R 2 in H63D human and H67D mouse carriers compared to WT-HFE controls.…”

Section: Discussionmentioning

confidence: 99%

Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice

Meadowcroft

Wang

Purnell

et al. 2015

Brain Imaging and Behavior

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Mutations within the HFE protein gene sequence have been associated with increased risk of developing a number of neurodegenerative disorders. To this effect, an animal model has been created which incorporates the mouse homologue to the human H63D-HFE mutation: the H67D-HFE knock-in mouse. These mice exhibit alterations in iron management proteins, have increased neuronal oxidative stress, and a disruption in cholesterol regulation. However, it remains undetermined how these differences translate to human H63D carriers in regards to white matter (WM) integrity. To this endeavor, MRI transverse relaxation rate (R2) parametrics were employed to test the hypothesis that WM alterations are present in H63D human carriers and are recapitulated in the H67D mice. H63D carriers exhibit widespread reductions in brain R2 compared to non-carriers within white matter association fibers in the brain. Similar R2 decreases within white matter tracks were observed in the H67D mouse brain. Additionally, an exacerbation of age-related R2 decrease is found in the H67D animal model in white matter regions of interest. The decrease in R2 within white matter tracks of both species is speculated to be multifaceted. The R2 changes are hypothesized to be due to alterations in axonal biochemical tissue composition. The R2 changes observed in both the human-H63D and mouse-H67D data suggest that modified white matter myelination is occurring in subjects with HFE mutations, potentially increasing vulnerability to neurodegenerative disorders.

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H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Cited by 27 publications

References 74 publications

HFE p.H63D polymorphism does not influence ALS phenotype and survival

HFE p.H63D polymorphism does not influence ALS phenotype and survival

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice

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