Abstract:Alzheimer's disease (AD) is widely held to be a disorder associated with oxidative stress due, in part, to the membrane action of amyloid~3-peptide (A/3). A~-associated free radicals cause lipid peroxidation, a major product of which is 4-hydroxy-2-trans-nonenal (HNE). We determined whether HNE would alter the conformation of synaptosomal membrane proteins, which might be related to the known neurotoxicity of A~3and HNE. Electron paramagnetic resonance spectroscopy, using a protein-specific spin label, MAL-6 (… Show more
“…24) From these findings, therefore, it is suggested that the lipid fluidity at the membrane surface decreased by modification of the synaptosomes with HNE. This finding is not consistent with the reports by Subramanian et al 25) and Buko et al, 26) in which they reported that modification of synaptosomal membranes 25) and liver plasma membranes 26) with HNE caused an increased lipid fluidity of the membranes.…”
The effects of lipid hydroperoxide degradation products, such as 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA), on bovine brain synaptosomal ATPase activities and their membrane lipid organization were examined. When the synaptosomes were treated with HNE, this resulted in the decrease of Na
“…24) From these findings, therefore, it is suggested that the lipid fluidity at the membrane surface decreased by modification of the synaptosomes with HNE. This finding is not consistent with the reports by Subramanian et al 25) and Buko et al, 26) in which they reported that modification of synaptosomal membranes 25) and liver plasma membranes 26) with HNE caused an increased lipid fluidity of the membranes.…”
The effects of lipid hydroperoxide degradation products, such as 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA), on bovine brain synaptosomal ATPase activities and their membrane lipid organization were examined. When the synaptosomes were treated with HNE, this resulted in the decrease of Na
“…Oxidatively modified proteins are generally dysfunctional, losing catalytic or structural integrity (29,51,52). Oxidative damage to proteins is of importance in explaining metabolic dysfunctions associated to oxidative stress-mediated diseases.…”
Huntington disease (HD) is a hereditary neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. The genetic defect responsible for the onset of the disease, expansion of CAG repeats in exon 1 of the gene that codes for huntingtin on chromosome 4, has been unambiguously identified. On the other hand, the mechanisms by which the mutation causes the disease are not completely understood yet. However, defects in energy metabolism of affected cells may cause oxidative damage, which has been proposed as one of the underlying molecular mechanisms that participate in the etiology of the disease. In our effort to investigate the extent of oxidative damage occurring at the protein level, we used a parallel proteomic approach to identify proteins potentially involved in processes upstream or downstream of the disease-causing huntingtin in a well established HD mouse model (R6/2 transgenic mice). We have demonstrated that the expression levels of dihydrolipoamide S-succinyltransferase and aspartate aminotransferase increase consistently over the course of disease (10-week-old mice). In contrast, pyruvate dehydrogenase expression levels were found to be decreased in 10-week-old HD transgenic mice compared with young (4-week-old) mice. Our experimental approach also led to the identification of oxidatively modified proteins. Six proteins were found to be significantly oxidized in old R6/2 transgenic mice compared with either young transgenic mice or non-transgenic mice. These proteins are ␣-enolase, ␥-enolase (neuron-specific enolase), aconitase, the voltage-dependent anion channel 1, heat shock protein 90, and creatine kinase. Because oxidative damage has proved to play an important role in the pathogenesis and the progression of Huntington disease, our results for the first time identify specific oxidatively modified proteins that potentially contribute to the pathogenesis of Huntington disease.
“…Through hydration, the C-O bond breaks, resulting in 4-hydroxy-2-nonenal. As noted, once formed, HNE can covalently attach to proteins by Michael addition, which alters protein structure (361) and causes a loss of protein function and activity (139).…”
Section: Hne Adduction To Proteinsmentioning
confidence: 93%
“…Protein-bound HNE in brain and progression of Alzheimer's disease. As just discussed, HNE is a reactive product of lipid peroxidation, and this a,b-unsaturated alkenal binds to Cys, His, or Lys residues of proteins, thereby changing the conformation and function of proteins (66,79,139,187,361). In AD, HNE has been found to be significantly elevated in AD brain, plasma, and CSF (187,238,297,348).…”
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.