Altered selenium status in Huntington's disease: Neuroprotection by selenite in the N171-82Q mouse model

Zhang, Lu; Marks, Eileen; Chen, Jianfang; Moline, Jenna; Barrows, Lorraine F.; Raisbeck, Merl F.; Volitakis, Irene; Cherny, Robert A.; Chopra, Vanita; Bush, Ashley I.; Hersch, Steven M.; Fox, Jonathan H.

doi:10.1016/j.nbd.2014.06.022

Cited by 42 publications

(30 citation statements)

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“…In this process, GSH is oxidized to GSSG (oxidized glutathione), an indicator of oxidative stress. GSSG is increased in a cell line model of HD [44] and also the brains of N171-82Q HD mice [23]. We found that iron supplemented HD mice had significant increases in cortical and striatal GSSG.…”

Section: Discussionmentioning

confidence: 53%

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Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease

et al. 2015

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Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion that encodes a polyglutamine tract in huntingtin (htt) protein. Dysregulation of brain iron homeostasis, oxidative stress and neurodegeneration are consistent features of the HD phenotype. Therefore, environmental factors that exacerbate oxidative stress and iron dysregulation may potentiate HD. Iron supplementation in the human population is common during infant and adult-life stages. In this study, iron supplementation in neonatal HD mice resulted in deterioration of spontaneous motor running activity, elevated levels of brain lactate and oxidized glutathione consistent with increased energetic dysfunction and oxidative stress, and increased striatal and motor cortical neuronal atrophy, collectively demonstrating potentiation of the disease phenotype. Oxidative stress, energetic, and anatomic markers of degeneration were not affected in wild-type littermate iron-supplemented mice. Further, there was no effect of elevated iron intake on disease outcomes in adult HD mice. We have demonstrated an interaction between the mutant huntingtin gene and iron supplementation in neonatal HD mice. Findings indicate that elevated neonatal iron intake potentiates mouse HD and promotes oxidative stress and energetic dysfunction in brain. Neonatal-infant dietary iron intake level may be an environmental modifier of human HD.

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Section: Discussionmentioning

confidence: 53%

“…Spontaneous cage wheel running activity was used as a measure of spontaneous activity as previously described [23]. Mice were placed individually in cages with wireless running wheels (Med Associates, Inc.) for 4 days.…”

Section: Methodsmentioning

confidence: 99%

Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease

et al. 2015

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“…Effects of iron supplementation on manganese, zinc and copper were not found (data not shown). Glutathione is an important aqueous phase antioxidant and changes in this system are present in both R6/2 and N171-82Q HD mice [9, 24]. We quantified glutathione (GSH) in brains of study mice.…”

Section: Resultsmentioning

confidence: 99%

Neonatal Iron Supplementation Induces Striatal Atrophy in Female YAC128 Huntington’s Disease Mice

Berggren

Zhang

Fox

et al. 2016

JHD

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BackgroundDysregulation of iron homeostasis is implicated in the pathogenesis of Huntington’s disease. We have previously shown that increased iron intake in R6/2 HD neonatal mice, but not adult R6/2 HD mice potentiates disease outcomes at 12-weeks of age corresponding to advanced HD [Redox Biol. 2015;4 : 363–74]. However, whether these findings extend to other HD models is unknown. In particular, it is unclear if increased neonatal iron intake can promote neurodegeneration in mouse HD models where disease onset is delayed to mid-adult life.ObjectiveTo determine if increased dietary iron intake in neonatal and adult life-stages potentiates HD in the slowly progressive YAC128 HD mouse model.MethodsFemale neonatal mice were supplemented daily from days 10–17 with 120 μg/g body weight of carbonyl iron. Adult mice were provided diets containing low (50 ppm), medium (150 ppm) and high (500 ppm) iron concentrations from 2-months of age. HD progression was determined using behavioral, brain morphometric and biochemical approaches.ResultsNeonatal-iron supplemented YAC128 HD mice had significantly lower striatal volumes and striatal neuronal cell body volumes as compared to control HD mice at 1-year of age. Neonatal-iron supplementation of HD mice had no effect on rota-rod motor endurance and brain iron or glutathione status. Adult iron intake level had no effect on HD progression. YAC128 HD mice had altered peripheral responses to iron intake compared to iron-matched wild-type controls.ConclusionsFemale YAC128 HD mice supplemented with nutritionally-relevant levels of iron as neonates demonstrate increased striatal degeneration 1-year later.

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“…192,193 Although Se levels in plasma were not different between HD patients and healthy controls, HD patients presented a decrease in regional brain Se content; specifically in the putamen, dorso-lateral prefrontal cortex, primary visual cortex, cingulate gyrus and cerebellum. 194 Treatment of N171-82Q HD mice with SeO 3 2À significantly protected against decreased brain weight and reduced Huntington protein aggregation and oxidised glutathione. 194 In another HD mice model (3-nitropropionic acid exposure) treatment with ((Z)-2,3-bis(4-chlorophenylselanyl)prop-2-en-1-ol)(bis selenide) improved locomotor activity and motor coordination, restored succinate dehydrogenase enzyme activity and protected against oxidative stress.…”

Section: Other Neurodegenerative Diseasesmentioning

confidence: 94%

Selenium, selenoproteins and neurodegenerative diseases

et al. 2015

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It is unsurprising that our understanding of the role of selenium in neurological function is somewhat immature, considering its relatively recent discovery as an essential element to human health. Selenocysteine, the 21st amino acid, is the defining feature of the 25 selenoprotein-encoding genes so far discovered within the human genome. The low abundance of these proteins in the brain belies the integral role they play in normal neurological function, from well-characterised antioxidant activity in the periphery to poorly understood mechanisms that modulate mitochondrial function and response to brain pathology. Selenium has been identified as playing a role in several neurodegenerative disorders, including Alzheimer's and Parkinson's disease, though its function as a 'cause or effect' of disease process remains unclear. This review discusses selenium metabolism in detail, specifically with regard to the role it plays within the central nervous system, and examines the most current literature investigating how selenium may be involved in chronic diseases of the central nervous system.

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Altered selenium status in Huntington's disease: Neuroprotection by selenite in the N171-82Q mouse model

Cited by 42 publications

References 47 publications

Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease

Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease

Neonatal Iron Supplementation Induces Striatal Atrophy in Female YAC128 Huntington’s Disease Mice

Selenium, selenoproteins and neurodegenerative diseases

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