6 research outputs found
Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease
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
Selenium Levels in Serum, Red Blood Cells, and Cerebrospinal Fluid of Alzheimer's Disease Patients: A Report from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL)
© 2017 - IOS Press and the authors. All rights reserved. Selenium (Se) protects cells against oxidative stress damage through a range of bioactive selenoproteins. Increased oxidative stress is a prominent feature of Alzheimer's disease (AD), and previous studies have shown that Se deficiency is associated with age-related cognitive decline. In this study, we assessed Se status in different biofluids from a subgroup of participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing. As Se in humans can either be an active component of selenoproteins or inactive via non-specific incorporation into other proteins, we used both size exclusion chromatography-inductively coupled plasma-mass spectrometry (SEC-ICP-MS) and tandem mass spectrometry to characterize selenoproteins in serum. We observed no differences in total Se concentration in serum or cerebrospinal fluid of AD subjects compared to mildly cognitively impairment patients and healthy controls. However, Se levels in erythrocytes were decreased in AD compared to controls. SEC-ICP-MS analysis revealed a dominant Se-containing fraction. This fraction was subjected to standard protein purification and a bottom-up proteomics approach to confirm that the abundant Se in the fraction was due, in part, to selenoprotein P. The lack of change in the Se level is at odds with our previous observations in a Brazilian population deficient in Se, and we attribute this to the Australian cohort being Se-replete
Characterization and Identification of Dityrosine Cross-Linked Peptides Using Tandem Mass Spectrometry
The use of mass spectrometry
coupled with chemical cross-linking
of proteins has become a powerful tool for proteins structure and
interactions studies. Unlike structural analysis of proteins using
chemical reagents specific for lysine or cysteine residues, identification
of gas-phase fragmentation patterns of endogenous dityrosine cross-linked
peptides have not been investigated. Dityrosine cross-linking in proteins
and peptides are clinical markers of oxidative stress, aging, and
neurodegenerative diseases including Alzheimer’s disease and
Parkinson’s disease. In this study, we investigated and characterized
the fragmentation pattern of a synthetically prepared dityrosine cross-linked
dimer of Aβ(1–16) using ESI tandem mass spectrometry.
We then detailed the fragmentation pattern of dityrosine cross-linked
Aβ(1–16), using collision induced dissociation (CID),
higher-energy collision induced dissociation (HCD), electron transfer
dissociation (ETD), and electron capture dissociation (ECD). Application
of these generic fragmentation rules of dityrosine cross-linked peptides
allowed for the identification of dityrosine cross-links in peptides
of Aβ and α-synuclein generated in vitro by enzymatic
peroxidation. We report, for the first time, the dityrosine cross-linked
residues in human hemoglobin and α-synuclein under oxidative
conditions. Together these tools open up the potential for automated
analysis of this naturally occurring post-translation modification
in neurodegenerative diseases as well as other pathological conditions