Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment

Singh, Inderjit; Paintlia, Ajaib S.; Khan, Mushfiquddin; Stanislaus, Romesh; Paintlia, Manjeet K.; Haq, Ehtishamul; Singh, Avtar; Contreras, Miguel Á.

doi:10.1016/j.brainres.2004.06.059

Cited by 60 publications

(61 citation statements)

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“…Our data (electron microscopy) indicate that peroxisomal population of twi livers is not significantly affected, suggesting that the observed decrease in peroxisomal protein, without alteration in peroxisome number, may not be related to an increase in the turnover/autophagy of the whole organelle, a mechanism that seems to regulate peroxisomal population [32,49,50]. However, it is consistent with previous findings described for CNS of animals models of neuroinflammatory disease [29,30].…”

Section: Discussionsupporting

confidence: 91%

“…Indeed, using three different animals models, i.e. acute endotoxemia in rat, and EAE model of multiple sclerosis and twitcher model of Krabbe disease, we have reported that mediators of inflammatory disease (cytokines, inducible-nitric oxide synthase) exert negative effects on peroxisomes, such as alteration in membrane properties and down regulation of proteins and hence, in their metabolic functions (fatty acids and eicosanoids β-oxidation; synthesis of plasmalogens and n-3 polyunsaturated fatty acids; and hydrogen peroxide detoxification) [29,30,32,47]. Our data (electron microscopy) indicate that peroxisomal population of twi livers is not significantly affected, suggesting that the observed decrease in peroxisomal protein, without alteration in peroxisome number, may not be related to an increase in the turnover/autophagy of the whole organelle, a mechanism that seems to regulate peroxisomal population [32,49,50].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, peroxisomes produce and detoxify hydrogen peroxide generated by the many oxidases that contain [17], and participate in the biosynthesis of important structural membrane constituents, such as the n-3 polyunsaturated fatty acid docosahexaenoic acid and plasmalogens [18,19]. Furthermore, their importance is underscored by the identification of fatal neurological diseases as a result of alterations of peroxisome biogenesis or proteins dysfunction [20,21]; and the role that peroxisomal metabolism play in brain myelination [22][23][24], brain cell homeostasis [25][26][27], and inflammation [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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Psychosine-induced alterations in peroxisomes of twitcher mouse liver

Contreras

Haq

Uto

et al. 2008

Archives of Biochemistry and Biophysics

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Krabbe's disease is a neuroinflammatory disorder in which galactosylsphingosine (psychosine) accumulates in nervous tissue. To gain insight into whether the psychosine-induced effects in nervous tissue extend to peripheral organs, we investigated the expression of cytokines and their effects on peroxisomal structure/function in twitcher mouse liver (animal model of Krabbe disease). Immunofluorescence analysis demonstrated TNF-α and IL-6 expression, which was confirmed by mRNAs quantitation. Despite the presence of TNF-α, lipidomic analysis did not indicate a significant decrease in sphingomyelin or an increase in ceramide fractions. Ultrastructural analysis of catalasedependent staining of liver sections showed reduced reactivity without significant changes in peroxisomal contents. This observation was confirmed by assaying catalase activity and quantitation of its mRNA, both of which were found significantly decreased in twitcher mouse liver. Western blot analysis demonstrated a generalized reduction of peroxisomal matrix and membrane proteins. These observations indicate that twitcher mouse pathobiology extends to the liver, where the induction of TNF-α and IL-6 compromise peroxisomal structure and function.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Psychosine-induced alterations in peroxisomes of twitcher mouse liver

Contreras

Haq

Uto

et al. 2008

Archives of Biochemistry and Biophysics

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“…This is supported by the fact that glycerol-3-phosphate-O-acyltransferase, a key enzyme in plasmalogen biosynthesis, is significantly down-regulated by TNFα (which was significantly upregulated during this study; Fig. 5) under in vitro and in vivo conditions [64,65]. Activation of a plasmalogen-specific phospholipase could be another factor contributing to plasmalogen loss under inflammatory conditions [41].…”

Section: Discussionsupporting

confidence: 56%

“…Activation of a plasmalogen-specific phospholipase could be another factor contributing to plasmalogen loss under inflammatory conditions [41]. [65]. Independent of the mechanism of plasmalogen loss, i.e., impaired synthesis or increased degradation/modification, the outcome for nervous system function is dismal.…”

mentioning

confidence: 99%

Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo

Üllen

Fauler

Köfeler

et al. 2010

Free Radical Biology and Medicine

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Plasmalogens, 1-O-alk-1′-enyl-2-acyl-sn-glycerophospholipids, are significant constituents of cellular membranes and are essential for normal brain development. Plasmalogens, which contain a vinyl ether bond at the sn-1 position, are preferential targets for hypochlorous acid (HOCl), generated by myeloperoxidase (MPO) from H 2 O 2 and chloride ions. Because MPO is implicated in neurodegeneration, this study pursued two aims: (i) to investigate the reactivity of mouse brain plasmalogens toward HOCl in vitro and (ii) to obtain in vivo evidence for MPO-mediated brain plasmalogen modification. Liquid chromatography coupled to hybrid linear ion trap-Fourier transform-ion cyclotron resonance mass spectrometry revealed plasmalogen modification in mouse brain lipid extracts at lower HOCl concentrations as observed for diacylphospholipids, resulting in the generation of 2-chloro fatty aldehydes and lysophospholipids. Lysophosphatidylethanolamine accumulation was transient, whereas lysophosphatidylcholine species containing saturated acyl residues remained stable. In vivo, a single, systemic endotoxin injection resulted in upregulation of cerebral MPO mRNA levels to a range comparable to that observed for tumor necrosis factor-α and cyclooxygenase-2. This inflammatory response was accompanied by a significant decrease in several brain plasmalogen species and concomitant in vivo generation of 2-chlorohexadecanal. The present findings demonstrate that activation of the MPO-H 2 O 2 -chloride system under neuroinflammatory conditions results in oxidative attack of the total cerebral plasmalogen pool. As this lipid class is indispensable for normal neuronal function, HOCl-mediated plasmalogen modification is likely to compromise normal synaptic transmission.© 2010 Elsevier Inc. All rights reserved. * Corresponding author. Fax: +43 316 380 9615. wolfgang.sattler@medunigraz.at. The mammalian brain is particularly sensitive toward oxidative damage, a result of the high oxygen demand and the high content of unsaturated lipids in the central nervous system (CNS) [1]. Potential sources of reactive species in the brain are mitochondria, amyloid-β peptides, redox-active iron, the NADPH-oxidase complex, and myeloperoxidase (MPO) [1][2][3]. MPO, a member of the heme peroxidase family, is present in the azurophilic granules of phagocytes, and H 2 O 2 -dependent oxidation of chloride ions to the powerful oxidant hypochlorous acid/hypochlorite (HOCl/OCl − ) is catalyzed by MPO. Under physiological conditions MPO-generated oxidants play an important role in killing invading pathogens, thereby contributing to host defense [3]. However, chronic activation of MPO results in elevated levels of reactive species, favoring chloramine formation, a modification potentially leading to tissue and/or organ injury [4][5][6][7][8]. Increasing evidence points toward MPO as a disease-amplifying enzyme in neurodegeneration [2]. In multiple sclerosis, MPO is present in microglia/macrophages at lesion sites [9,10] and cortical demyelination is associa...

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From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

2017

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The emerging diverse roles of ether (phospho)lipids in nervous system development and function in health and disease are currently attracting growing interest. Plasmalogens, a subgroup of ether lipids, are important membrane components involved in vesicle fusion and membrane raft composition. They store polyunsaturated fatty acids and may serve as antioxidants. Ether lipid metabolites act as precursors for the formation of glycosyl-phosphatidyl-inositol anchors; others, like platelet-activating factor, are implicated in signaling functions. Consolidating the available information, we attempt to provide molecular explanations for the dramatic neurological phenotype in ether lipid-deficient human patients and mice by linking individual functional properties of ether lipids with pathological features. Furthermore, recent publications have identified altered ether lipid levels in the context of many acquired neurological disorders including Alzheimer's disease (AD) and autism. Finally, current efforts to restore ether lipids in peroxisomal disorders as well as AD are critically reviewed.

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Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment

Cited by 60 publications

References 61 publications

Psychosine-induced alterations in peroxisomes of twitcher mouse liver

Psychosine-induced alterations in peroxisomes of twitcher mouse liver

Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

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