Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

Heidari, Mohsen; Johnstone, Daniel M.; Bassett, Brianna; Graham, Ross M.; Chua, Anita; House, Michael J.; Collingwood, Joanna F.; Bettencourt, Conceição; Houlden, Henry; Ryten, Mina; Olynyk, John K.; Trinder, Debbie; Milward, Elizabeth A.

doi:10.1038/mp.2015.192

Cited by 47 publications

(55 citation statements)

References 72 publications

(105 reference statements)

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“…Similarly, some hemochromatosis patients display schizophrenia-like or bipolar symptoms (76,77). In rodents, Heidari et al (78) found that Hfe 2/2 xTfr2 mut mice with brain iron overload are hyperactive. However, mixed results also exist; iron overload is associated with hypoactivity, increased anxiety, or no change in emotional behavior.…”

Section: Discussionmentioning

confidence: 99%

Brain iron loading impairs DNA methylation and alters GABAergic function in mice

Trivedi

Zhang

et al. 2018

FASEB j.

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Iron deficiency is closely associated with altered GABA metabolism and affective behavior. While mutation in the hemochromatosis (HFE) gene disrupts iron homeostasis and promotes oxidative stress that increases the risk of neurodegeneration, it is largely unknown whether HFE mutation modifies GABAergic homeostasis and emotional behavior. The goal of our study was to investigate the impact of HFE on GABAergic neurochemistry and redox–epigenetic regulation in the brain using H67D HFE‐mutant mice that recapitulates the H63D‐HFE mutation in humans. H67D mice displayed elevated redox‐active iron levels in the brain by 32% compared to age‐matched wild‐type mice. Moreover, the H67D brain had increased isoprostane and decreased glutathione, indicating elevated oxidative stress. Additionally, the H67D brain had decreased global methylation and attenuated DNA methyltransferase (DNMT) activity. Direct addition of iron to purified DNMT in vitro decreased enzyme activity in a concentration‐dependent manner. Last, H67D mice exhibited decreased anxiety‐like behavior, which was associated with increased expression of the GABAA receptor α2 subunits by 93%, and these changes were also observed in H67D mice fed a low‐iron diet. Taken together, our results suggest a putative role of HFE in regulating labile iron status in the brain, and mutation in H67D perturbs redox‐methylation status, contributing to GABAergic dysfunction.—Ye, Q., Trivedi, M., Zhang, Y., Böhlke, M., Alsulimani, H., Chang, J., Maher, T., Deth, R., Kim, J. Brain iron loading impairs DNA methylation and alters GABAergic function in mice. FASEB J. 33, 2460–2471 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Brain iron loading impairs DNA methylation and alters GABAergic function in mice

Trivedi

Zhang

et al. 2018

FASEB j.

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“…These pathologies together can generate mixed-signal and may lead to such discrepancies as observed between R3 and R1, R2 (76, 77). In areas with increased GFAP activity the magnetic susceptibility signature of iron and myelin changes and it is difficult to isolate myelin from iron during the pathological cascade groups (78,79). Also, in white matter, iron deposition has been shownto be minimal compared to the known demyelination process (36).…”

Section: Axonal Damage and Myelin Fragmentationmentioning

confidence: 99%

Combined Diffusion Tensor Imaging and Quantitative Susceptibility Mapping Discern Discrete Facets of White Matter Pathology Post-injury in the Rodent Brain

Soni

Vegh

et al. 2020

Front. Neurol.

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Early loss of white matter microstructure integrity is a significant cause of long-term neurological disorders following traumatic brain injury (TBI). White matter abnormalities typically involve axonal loss and demyelination. In-vivo imaging tools to detect and differentiate such microstructural changes are not well-explored. This work utilizes the conjoint potential offered by advanced magnetic resonance imaging techniques, including quantitative susceptibility mapping (QSM) and diffusion tensor imaging (DTI), to discern the underlying white matter pathology at specific time points (5 h, 1, 3, 7, 14, and 30 days) post-injury in the controlled cortical impact mouse model. A total of 42 animals were randomized into six TBI groups (n = 6 per group) and one sham group (n = 6). Histopathology was performed to validate in-vivo findings by performing myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP) immunostaining for the assessment of changes to myelin and astrocytes. After 5 h of injury radial diffusivity (RD) was increased in white matter without a significant change in axial diffusivity (AxD) and susceptibility values. After 1 day post-injury RD was decreased. AxD and susceptibility changes were seen after 3 days post-injury. Susceptibility increases in white matter were observed in both ipsilateral and contralateral regions and persisted for 30 days. In histology, an increase in GFAP immunoreactivity was observed after 3 days post-injury and remained high for 30 days in both ipsilateral and contralateral white matter regions. A loss in MBP signal was noted after 3 days post-injury that continued up to 30 days. In conclusion, these results demonstrate the complementary ability of DTI and QSM in discerning the micro-pathological processes triggered following TBI. While DTI revealed acute and focal white matter changes, QSM mirrored the temporal demyelination in the white matter tracts and diffuse regions at the chronic state.

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“…On the other hand, excessive iron concentration in macrophages may promote a pro-inflammatory M1 activation state and facilitate inflammation [167]. In an animal model of cerebral iron overload, expression of several NBIA-related proteins involved in phospholipid and myelin metabolism was decreased suggesting that iron accumulation may influence myelin synthesis and maintenance [168]. Several studies showed that chelators ameliorate experimental autoimmune encephalomyelitis which is an animal model of MS.…”

Section: Multiple Sclerosismentioning

confidence: 99%

Iron chelation in the treatment of neurodegenerative diseases

Dušek

Schneider

Aaseth

2016

Journal of Trace Elements in Medicine and Biology

106

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a b s t r a c tDisturbance of cerebral iron regulation is almost universal in neurodegenerative disorders. There is a growing body of evidence that increased iron deposits may contribute to degenerative changes. Thus, the effect of iron chelation therapy has been investigated in many neurological disorders including rare genetic syndromes with neurodegeneration with brain iron accumulation as well as common sporadic disorders such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. This review summarizes recent advances in understanding the role of iron in the etiology of neurodegeneration. Outcomes of studies investigating the effect of iron chelation therapy in neurodegenerative disorders are systematically presented in tables. Iron chelators, particularly the blood brain barrier-crossing compound deferiprone, are capable of decreasing cerebral iron in areas with abnormally high concentrations as documented by MRI. Yet, currently, there is no compelling evidence of the clinical effect of iron removal therapy on any neurological disorder. However, several studies indicate that it may prevent or slow down disease progression of several disorders such as aceruloplasminemia, pantothenate kinase-associated neurodegeneration or Parkinson's disease.

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Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

Cited by 47 publications

References 72 publications

Brain iron loading impairs DNA methylation and alters GABAergic function in mice

Brain iron loading impairs DNA methylation and alters GABAergic function in mice

Combined Diffusion Tensor Imaging and Quantitative Susceptibility Mapping Discern Discrete Facets of White Matter Pathology Post-injury in the Rodent Brain

Iron chelation in the treatment of neurodegenerative diseases

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