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ABSTRACT: Alzheimer disease (AD) is an age-related neurodegenerative disease characterized by cognitive impairment that affects the life and activities of the affected individuals and their families. One of the main histopathological hallmarks of AD is the presence of senile plaques (SP). The main component of SP is amyloid beta-peptide (Aβ) that is derived from the proteolytic cleavage of amyloid precursor protein (APP). Studies conducted so far are consistent with the notion that methionine present at 35 position of Aβ is critical to Aβ-induced oxidative stress, and neurotoxicity. This review focuses on importance of methionine in the Abeta-induced oxidative stress. Further, we also discussed about signatures of oxidatively modified proteins, identified using redox proteomics approach, during the progression of AD. However, the exact relationship of the specifically oxidatively modified proteins in AD pathogenesis is poorly understood. Further studies are needed to address if the therapies directed towards oxidative stress and the associated target proteins might help to delay or prevent the progression and pathogenesis of AD.
Antioxidants & Redox Signaling 12/2012; · 8.20 Impact Factor
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ABSTRACT: Abstract Proteins are major targets of reactive oxygen and nitrogen species (ROS/RNS) and numerous post-translational, reversible or irreversible modifications have been characterized, which may lead to a change in the structure and/or function of the oxidized protein. Redox proteomics is an increasingly emerging branch of proteomics aimed at identifying and quantifying redox-based changes within the proteome both in redox signaling and under oxidative stress conditions. Correlation between protein oxidation and human disease is widely accepted, although elucidating cause and effect remains a challenge. Increasing biomedical data have provided compelling evidences for the involvement of perturbations in redox homeostasis in a large number of pathophysiological conditions and aging. Research toward a better understanding of the molecular mechanisms of a disease together with identification of specific targets of oxidative damage is urgently required. This is the power and potential of redox proteomics. In the last few years, combined proteomics, mass spectrometry (MS), and affinity chemistry-based methodologies have contributed in a significant way to provide a better understanding of protein oxidative modifications occurring in various biological specimens under different physiological and pathological conditions. Hence, this Forum on Redox Proteomics is timely. Original and review articles are presented on various subjects ranging from redox proteomics studies of oxidatively modified brain proteins in Alzheimer disease and animal models of Alzheimer and Parkinson disease, to potential new biomarker discovery paradigm for human disease, to chronic kidney disease, to protein nitration in aging and age-related neurodegenerative disorders, electrophile-responsive proteomes of special relevance to diseases involving mitochondrial alterations, to cardiovascular physiology and pathology. Antioxid. Redox Signal. 17, 1487-1489.
Antioxidants & Redox Signaling 06/2012; 17(11):1487-9. · 8.20 Impact Factor
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Rukhsana Sultana,
Renã A S Robinson,
Miranda Bader Lange,
Ada Fiorini,
Veronica Galvan,
Joanna Fombonne,
Austin Baker,
Olivia Gorostiza,
Junli Zhang,
Jian Cai,
William M Pierce,
Dale E Bredesen, D Allan Butterfield
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ABSTRACT: Abstract The single methionine (Met/M) residue of amyloid-beta (Aβ) peptide, at position 35 of the 42-mer, has important relevance for Aβ-induced oxidative stress and neurotoxicity. Recent in vivo brain studies in a transgenic (Tg) Alzheimer disease (AD) mouse model with Swedish and Indiana familial AD mutations in human amyloid precursor protein (APP) (referred to as the J20 Tg mouse) demonstrated increased levels of oxidative stress. However, the substitution of the Met631 residue of APP to leucine (Leu/L) (M631L in human APP numbering, referred to as M631L Tg and corresponding to residue 35 of Aβ1-42) resulted in no significant in vivo oxidative stress levels, thereby supporting the hypothesis that Met-35 of Aβ contributes to oxidative insult in the AD brain. It is conceivable that oxidative stress mediated by Met-35 of Aβ is important in regulating numerous downstream effects, leading to differential levels of relevant biochemical pathways in AD. Therefore, in the current study using proteomics, we tested the hypothesis that several brain proteins involved in pathways such as energy and metabolism, antioxidant activity, proteasome degradation, and pH regulation are altered in J20Tg versus M631L Tg AD mice. Antioxid. Redox Signal. 17, 1507-1514.
Antioxidants & Redox Signaling 04/2012; 17(11):1507-14. · 8.20 Impact Factor
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Fabio Di Domenico,
Rukhsana Sultana,
Andrew Ferree,
Katelyn Smith,
Eugenio Barone,
Marzia Perluigi,
Raffaella Coccia,
William Pierce,
Jian Cai,
Cesare Mancuso,
Rachel Squillace,
Manfred Wiengele,
Isabella Dalle-Donne,
Benjamin Wolozin, D Allan Butterfield
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ABSTRACT: Abstract Aims: The human LRRK2 gene has been identified as the most common causative gene of autosomal-dominantly inherited and idiopathic Parkinson disease (PD). The G2019S substitution is the most common mutation in LRRK2. The R1441C mutation also occurs in cases of familial PD, but is not as prevalent. Some cases of LRRK2-based PD exhibit Tau pathology, which suggests that alterations on LRRK2 activity affect the pathophysiology of Tau. To investigate how LRRK2 might affect Tau and the pathophysiology of PD, we generated lines of C. elegans expressing human LRRK2 [wild-type (WT) or mutated (G2019S or R1441C)] with and without V337M Tau. Expression and redox proteomics were used to identify the effects of LRRK2 (WT and mutant) on protein expression and oxidative modifications. Results: Co-expression of WT LRRK2 and Tau led to increased expression of numerous proteins, including several 60S ribosomal proteins, mitochondrial proteins, and the V-type proton ATPase, which is associated with autophagy. C. elegans expressing mutant LRRK2 showed similar changes, but also showed increased protein oxidation and lipid peroxidation, the latter indexed as increased protein-bound 4-hydroxy-2-nonenal (HNE). Innovation: Our study brings new knowledge about the possible alterations induced by LRRK2 (WT and mutated) and Tau interactions, suggesting the involvement of G2019S and R1441C in Tau-dependent neurodegenerative processes. Conclusion: These results suggest that changes in LRRK2 expression or activity lead to corresponding changes in mitochondrial function, autophagy, and protein translation. These findings are discussed with reference to the pathophysiology of PD. Antioxid. Redox Signal. 17, 1490-1506.
Antioxidants & Redox Signaling 02/2012; 17(11):1490-506. · 8.20 Impact Factor
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ABSTRACT: Abstract Significance: Among different forms of oxidative stress, lipid peroxidation comprises the interaction of free radicals with polyunsaturated fatty acids, which in turn leads to the formation of highly reactive electrophilic aldehydes. Among these, the most abundant aldehydes are 4-hydroxy-2-nonenal (HNE) and malondialdehyde, while acrolein is the most reactive. HNE is considered a robust marker of oxidative stress and a toxic compound for several cell types. Proteins are particularly susceptible to modification caused by HNE, and adduct formation plays a critical role in multiple cellular processes. Recent Advances: With the outstanding progress of proteomics, the identification of putative biomarkers for neurodegenerative disorders has been the main focus of several studies and will continue to be a difficult task. Critical Issues: The present review focuses on the role of lipid peroxidation, particularly of HNE-induced protein modification, in neurodegenerative diseases. By comparing results obtained in different neurodegenerative diseases, it may be possible to identify both similarities and specific differences in addition to better characterize selective neurodegenerative phenomena associated with protein dysfunction. Results obtained in our laboratory and others support the common deregulation of energy metabolism and mitochondrial function in neurodegeneration. Future Directions: Research towards a better understanding of the molecular mechanisms involved in neurodegeneration together with identification of specific targets of oxidative damage is urgently required. Redox proteomics will contribute to broaden the knowledge in regard to potential biomarkers for disease diagnosis and may also provide insight into damaged metabolic networks and potential targets for modulation of disease progression. Antioxid. Redox Signal. 17, 1590-1609.
Antioxidants & Redox Signaling 11/2011; 17(11):1590-609. · 8.20 Impact Factor
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ABSTRACT: Abstract 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 oxidative-stress-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.
Antioxidants & Redox Signaling 11/2011; 17(11):1610-55. · 8.20 Impact Factor
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ABSTRACT: Previous studies indicated increased levels of protein oxidation in brain from subjects with Alzheimer's disease (AD), raising the question of whether oxidative damage is a late effect of neurodegeneration or precedes and contributes to the pathogenesis of AD. Hence, in the present study we used a parallel proteomic approach to identify oxidatively modified proteins in inferior parietal lobule (IPL) from subjects with mild cognitive impairment (MCI) and early stage-AD (EAD). By comparing to age-matched controls, we reasoned that such analysis could help in understanding potential mechanisms involved in upstream processes in AD pathogenesis. We have identified four proteins that showed elevated levels of protein carbonyls: carbonic anhydrase II (CA II), heat shock protein 70 (Hsp70), mitogen-activated protein kinase I (MAPKI), and syntaxin binding protein I (SBP1) in MCI IPL. In EAD IPL we identified three proteins: phosphoglycerate mutase 1 (PM1), glial fibrillary acidic protein, and fructose bisphospate aldolase C (FBA-C). Our results imply that some of the common targets of protein carbonylation correlated with AD neuropathology and suggest a possible involvement of protein modifications in the AD progression.
Antioxidants & Redox Signaling 09/2009; 12(3):327-36. · 8.20 Impact Factor
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ECU Publications.
