Reductions in neuronal peroxisomes in multiple sclerosis grey matter

Gray, Elizabeth; Rice, Claire M; Hares, Kelly M; Redondo, Juliana; Kemp, Kevin C; Williams, Marcus; Brown, Andrew; Scolding, Neil; Wilkins, Alastair

doi:10.1177/1352458513505691

Cited by 43 publications

(34 citation statements)

References 29 publications

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“…As the expression of the Abcd3 transporter is considered a suitable marker to evaluate peroxisomal mass, which can reflect peroxisomal biogenesis [63], the ability of 7KC to modulate the number of peroxisomes and/or peroxisomal mass was determined by flow cytometry with antibodies raised against Abcd3: the quantification of the mean fluorescence intensity (MFI) and the percentage of Abcd3 negative cells were determined (Figure 3). Under treatment with 7KC, the MFI of Abcd3-cells was decreased (Figure 3A) and the percentage of Abcd3-negative cells was increased (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“…As expected, Trolox did not restore the marked decrease in Abcd1 and Abcd2 mRNAs levels induced by 7KC (50 μM), or the slight decrease in the Mfp2 mRNA level induced by 7KC (50 μM) (Figure 5). In addition, as Abcd3 protein, considered a suitable marker of peroxisomal mass [63], was decreased as determined by flow cytometry and Western blotting, its mRNA level was also quantified (Ct value of Abcd3 in untreated BV-2 cells = 26.5 ± 0.7): under treatment with 7KC, no significant modification of the Abcd3 mRNA level was observed, and no effect of α-tocopherol, γ-tocopherol, Trolox and OA on the Abcd3 mRNA level was found (Figure 4). …”

Section: Resultsmentioning

confidence: 99%

“…As 7KC could contribute to the pathophysiology of MS and X-ALD [21,22], we wondered whether it could have various side effects on the peroxisome, which is essential for RedOx homeostasis and the synthesis of myelin by oligodendrocytes [66,94] and whose deficiency in nerve cells of the brain produces astrogliosis and gliosis associated with inflammatory processes in the central nervous system [67]. As deficient peroxisomal β-oxidation fosters the accumulation of very long chain fatty acids (VLCFA) in X-ALD patients, and might also occur in patients with dementia and MS [95,96,97], we determined by RT-qPCR and/or flow cytometry the impact of 7KC on mRNA and/or protein levels of Abcd1, Abcd2, Mfp2 and Acox1, which are involved in the peroxisomal β-oxidation pathway of VLCFA [64,98] and of Abcd3 used as a marker of peroxisomal mass [63]. In agreement with our previous data, which also included protein analysis of Abcd1, Abcd2, and Abcd3 by Western blot as well as the measurement of catalase and Acox1 activities [22], we found marked decreases in Abcd1, Abcd2, Mfp2 mRNAs levels, suggesting impaired β-oxidation in 7KC-treated BV-2 cells.…”

Section: Resultsmentioning

confidence: 99%

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Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells

Debbabi

Nury

Zarrouk

et al. 2016

IJMS

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Lipid peroxidation products, such as 7-ketocholesterol (7KC), may be increased in the body fluids and tissues of patients with neurodegenerative diseases and trigger microglial dysfunction involved in neurodegeneration. It is therefore important to identify synthetic and natural molecules able to impair the toxic effects of 7KC. We determined the impact of 7KC on murine microglial BV-2 cells, especially its ability to trigger mitochondrial and peroxisomal dysfunction, and evaluated the protective effects of α- and γ-tocopherol, Trolox, and oleic acid (OA). Multiple complementary chemical assays, flow cytometric and biochemical methods were used to evaluate the antioxidant and cytoprotective properties of these molecules. According to various complementary assays to estimate antioxidant activity, only α-, and γ-tocopherol, and Trolox had antioxidant properties. However, only α-tocopherol, γ-tocopherol and OA were able to impair 7KC-induced loss of mitochondrial transmembrane potential, which is associated with increased permeability to propidium iodide, an indicator of cell death. In addition, α-and γ-tocopherol, and OA were able to prevent the decrease in Abcd3 protein levels, which allows the measurement of peroxisomal mass, and in mRNA levels of Abcd1 and Abcd2, which encode for two transporters involved in peroxisomal β-oxidation. Thus, 7KC-induced side effects are associated with mitochondrial and peroxisomal dysfunction which can be inversed by natural compounds, thus supporting the hypothesis that the composition of the diet can act on the function of organelles involved in neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells

Debbabi

Nury

Zarrouk

et al. 2016

IJMS

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“…Moreover, an alteration in peroxisomal protein contents (induction of ABCD3, Acyl-coA oxidase and Pex5, concomitant with a 25 reduction of thiolase and catalase in the hippocampus) was readily observed at early stages of pathology in the Tg2576 AD mouse model [164]. In MS patients, VLCFA are increased in grey matter, consistent with a decrease of peroxisomes in grey matter neurons [165]. Peroxisomes have also been linked to PD [132].…”

Section: The Role Of Peroxisomes In Neurodegenerationmentioning

confidence: 92%

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

Fourcade

Ferrer

Pujol

2015

Free Radical Biology and Medicine

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Peroxisomal and mitochondrial malfunction, which are highly intertwined through redox regulation, in combination with defective proteostasis, are hallmarks of the most prevalent multifactorial neurodegenerative diseases-including Alzheimer's (AD) and Parkinson's disease (PD)-and of the aging process, and are also found in inherited conditions. Here we review the interplay between oxidative stress and axonal degeneration, taking as groundwork recent findings on pathomechanisms of the peroxisomal neurometabolic disease adrenoleukodystrophy (X-ALD). We explore the impact of chronic redox imbalance caused by the excess of very long-chain fatty acids (VLCFA) on mitochondrial respiration and biogenesis, and discuss how this impairs protein quality control mechanisms essential for neural cell survival, such as the proteasome and autophagy systems. As consequence, prime molecular targets in the pathogenetic cascade emerge, such as the SIRT1/PGC-1α axis of mitochondrial biogenesis, and the inhibitor of autophagy mTOR. Thus, we propose that mitochondria-targeted antioxidants; mitochondrial biogenesis boosters such as the antidiabetic pioglitazone and the SIRT1 ligand resveratrol; and the autophagy activator temsirolimus, a derivative of the mTOR inhibitor rapamycin, hold promise as disease-modifying therapies for X-ALD.

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“…Erre mutatunk be néhány példát az 1. táblázatban [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26].…”

Section: öSszefoglaló Közleményunclassified

A vér–agy gát működése, öregedése és diszfunkciója. Átjutás a barrieren

Hutka

Dénès

2016

Orvosi Hetilap

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Az agy és a keringés kapcsolatát biztosító, mikroerek szintjén megjelenő védelmi vonal a vér-agy gát, amely az idegrendszer homeosztázisának fenntartásában, az agy védelmében, táplálásában és finoman regulált működésének biztosításában játszik jelentős szerepet. Funkcióját számos sejttípus összehangolt működése és molekuláris rendszerek szabályozott kifejeződése teszi lehetővé. Azonban ez a komplex rendszer bizonyos behatásokra károsodik, szerkezete megbomlik, s akkor a védelmi struktúra permeabilitása megnő. Ez nemkívánatos exogén és endogén anyagok idegrendszeri megjelenését vagy szintjének emelkedését eredményezi, amely számos akut és krónikus központi idegrendszeri betegség patomechanizmusában játszik szerepet. A vér-agy gát károsodásának legfőbb rizikófaktora maga az öregedés, amely DNS-mutáción, oxidatív károsodáson és gyulladásos mediátorok megjelenésén keresztül destrukturálja a védelmi rendszert. Ez bizonyos fokig a természetes öregedés velejárója, de a membrántranszporterek műkö-désének diszfunkciója patológiás állapotok kialakulásához is vezethet, amely a krónikus neurodegeneratív betegségek oki tényezői között szerepel. Ebben a közleményben a vér-agy gát felépítését, működését, károsodását és az agyi gyógyszerbeviteli lehetőségeket foglaljuk össze. Orv. Hetil., 2016, 157(51), 2019-2027. Kulcsszavak: vér-agy gát, membrántranszporterek, öregedés, gyógyszerátvitel a vér-agy gáton Function, aging and dysfunction of blood-brain barrier. Crossing the barrierThe blood-brain barrier is an interface between the circulation and brain. It is responsible for the homeostasis of central nervous system, protection and feeding of the brain and for providing the conditions for fine regulation of neurons. The coordinated function of different cell types and the regulated expression of molecular systems make possible the functionality of blood-brain barrier. However, this complex system can be broken due to different insults with a consequence of appearance of elevated levels of unwanted exogenous and endogenous molecules in the brain involved in the pathomechanisms of several disorders. The most important risk factor for the damage of blood-brain barrier is the aging itself, which causes disruption of the barrier through DNA mutation, oxidative stress and release of inflammatory mediators. Although the physiological aging is accompanied by morphological changes, the dysfunction of membrane transporters could also lead to neurodegenerative disorders. Structure, function and breakdown of the blood-brain barrier and the possibilities to cross it, are presented.Keywords: blood-brain barrier, membrane transporter proteins, aging, drug delivery , F., Hutka, B., Dénes, L. [Function, aging and dysfunction of blood-brain barrier. Crossing the barrier]. Orv. Hetil., 2016, 157(51), 2019-2027. (Beérkezett: 2016 elfogadva: 2016. Rövidítések Ang-1 = angiopoetin-1, a vascularis növekedési faktorok egyik típusa, az embrionális fejlődésben van szerepe; AQP-4 = aquaporin-4, membránprotein, amely a vízmolekulákat átvezeti a membrá...

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Reductions in neuronal peroxisomes in multiple sclerosis grey matter

Abstract: Collectively, these observations provide evidence that there is an overall reduction in peroxisomal gene expression and peroxisomal proteins in GM neurons in MS. Changes in peroxisomal function may contribute to neuronal dysfunction and degeneration in MS.

Cited by 43 publications

References 29 publications

Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells

Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells

Oxidative stress, mitochondrial and proteostasis malfunction in adrenoleukodystrophy: A paradigm for axonal degeneration

A vér–agy gát működése, öregedése és diszfunkciója. Átjutás a barrieren

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