Effects of hemochromatosis and transferrin gene mutations on iron dyshomeostasis, liver dysfunction and on the risk of Alzheimer's disease

Giambattistelli, Federica; Bucossi, Serena; Salustri, Carlo; Panetta, Valentina; Mariani, Stefania; Siotto, Mariacristina; Ventriglia, Mariacarla; Vernieri, Fabrizio; Dell’Acqua, Maria Luisa; Cassetta, Emanuele; Rossini, Paolo Maria; Squitti, Rosanna

doi:10.1016/j.neurobiolaging.2011.03.005

Cited by 60 publications

(47 citation statements)

References 49 publications

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“…Further, T2 in the subiculum of adult APP/PS1 animals was lower than in PS1 mice, suggesting a relationship between amyloid and iron loads in this region (137). AD patients who were carriers of the HFE mutation showed higher levels of iron, lower levels of transferrin (TF) and ceruloplasmin (CP), and higher CP/TF ratios, suggesting a link between HFE mutations and iron abnormalities, and OS in AD (167). Further, the iron transport protein TF functions were also reported to be disrupted in AD (108).…”

Section: E Role Of Iron In Neurodegenerationmentioning

confidence: 99%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

157

142

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Several studies demonstrated that oxidative damage is a characteristic feature of many neurodegenerative diseases. The accumulation of oxidatively modified proteins may disrupt cellular functions by affecting protein expression, protein turnover, cell signaling, and induction of apoptosis and necrosis, suggesting that protein oxidation could have both physiological and pathological significance. For nearly two decades, our laboratory focused particular attention on studying oxidative damage of proteins and how their chemical modifications induced by reactive oxygen species/reactive nitrogen species correlate with pathology, biochemical alterations, and clinical presentations of Alzheimer's disease. This comprehensive article outlines basic knowledge of oxidative modification of proteins and lipids, followed by the principles of redox proteomics analysis, which also involve recent advances of mass spectrometry technology, and its application to selected age-related neurodegenerative diseases. Redox proteomics results obtained in different diseases and animal models thereof may provide new insights into the main mechanisms involved in the pathogenesis and progression of oxidativestress-related neurodegenerative disorders. Redox proteomics can be considered a multifaceted approach that has the potential to provide insights into the molecular mechanisms of a disease, to find disease markers, as well as to identify potential targets for drug therapy. Considering the importance of a better understanding of the cause/effect of protein dysfunction in the pathogenesis and progression of neurodegenerative disorders, this article provides an overview of the intrinsic power of the redox proteomics approach together with the most significant results obtained by our laboratory and others during almost 10 years of research on neurodegenerative disorders since we initiated the field of redox proteomics. Antioxid. Redox Signal. 17, 1610-1655.

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Section: E Role Of Iron In Neurodegenerationmentioning

confidence: 99%

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Butterfield

Perluigi

Reed

et al. 2012

Antioxidants & Redox Signaling

157

142

View full text Add to dashboard Cite

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“…16 All AD patients had been diagnosed as ''probable AD'' according to National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria 17,18 and had an MiniMental State Examination (MMSE) score £ 25. 19 All AD patients underwent general medical, neurologic, and psychiatric assessments.…”

Section: Subjectsmentioning

confidence: 99%

Linkage Disequilibrium and Haplotype Analysis of theATP7BGene in Alzheimer's Disease

Squitti

Polimanti

Bucossi

et al. 2013

Rejuvenation Research

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Copper dyshomeostasis leading to a labile Cu 2 + not bound to ceruloplasmin (''free'' copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case-control population (n = 515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two ''strong LD'' blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR] = 1.52, 95% confidence interval [CI] = 1.10-2.09, p = 0.010; rs2147363, OR = 1.58, 95% CI = 1.11-2.25, p = 0.010; rs1061472, OR = 1.73, 95% CI = 1.23-2.43, p = 0.002; rs732774, OR = 2.31, 95% CI = 1.41-3.77, p < 0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.

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“…In a recent study of HFE and TF variants on iron levels and risk for AD, Giambattistelli et al (52) found that patients with AD with the H63D polymorphism had increased plasma iron and transferrin levels, but this pattern was not found in healthy control subjects with the variant; in fact, a meta-analysis found that the H63D polymorphism may be protective against AD (53). As shown in Table S1, the minor allele at rs1799945 (H63D) showed a positive effect on FA.…”

Section: Genetic Factorsmentioning

confidence: 99%

Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in theHFEgene

Jahanshad

Kohannim

Hibar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Control of iron homeostasis is essential for healthy central nervous system function: iron deficiency is associated with cognitive impairment, yet iron overload is thought to promote neurodegenerative diseases. Specific genetic markers have been previously identified that influence levels of transferrin, the protein that transports iron throughout the body, in the blood and brain. Here, we discovered that transferrin levels are related to detectable differences in the macro-and microstructure of the living brain. We collected brain MRI scans from 615 healthy young adult twins and siblings, of whom 574 were also scanned with diffusion tensor imaging at 4 Tesla. Fiber integrity was assessed by using the diffusion tensor imaging-based measure of fractional anisotropy. In bivariate genetic models based on monozygotic and dizygotic twins, we discovered that partially overlapping additive genetic factors influenced transferrin levels and brain microstructure. We also examined common variants in genes associated with transferrin levels, TF and HFE, and found that a commonly carried polymorphism (H63D at rs1799945) in the hemochromatotic HFE gene was associated with white matter fiber integrity. This gene has a well documented association with iron overload. Our statistical maps reveal previously unknown influences of the same gene on brain microstructure and transferrin levels. This discovery may shed light on the neural mechanisms by which iron affects cognition, neurodevelopment, and neurodegeneration.neuroimaging genetics | twin modeling | pathway analysis | tensor-based morphometry | voxel based analysis

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Effects of hemochromatosis and transferrin gene mutations on iron dyshomeostasis, liver dysfunction and on the risk of Alzheimer's disease

Cited by 60 publications

References 49 publications

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

Linkage Disequilibrium and Haplotype Analysis of theATP7BGene in Alzheimer's Disease

Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in theHFEgene

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