The cerebral lesions in a patient with generalized glutathione deficiency and pyroglutamic aciduria (5-oxoprolinuria)

Skullerud, Kari; Marstein, Sverre; Schrader, Harald; Brundelet, Pablo Jiménez; Jellum, Egil

doi:10.1007/bf00705812

Cited by 51 publications

(16 citation statements)

References 19 publications

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“…The brain efflux index method has demonstrated that L-Glu undergoes efflux from brain to blood (Hosoya et al, 1999). Moreover, O'Kane et al (1999) suggested that excitatory amino acid transporter subtypes 1ϳ3 are present on the abluminal (brain) side of the BBB and mediate brain-to-blood efflux transport of L-Glu. A (Skullerud et al, 1980). Therefore, under oxidative stress conditions, system x c Ϫ is likely to be induced at the BBB to supply L-cystine/L-Cys to the brain as well as the brain endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…Under oxidative stress in the brain, L-cystine and/or L-Cys need to undergo influx transport from the circulating blood to the brain across the blood-brain barrier (BBB) to synthesize glutathione as a protection against free radicals, peroxides, and other toxic compounds in the central nervous system (CNS) (Meister and Anderson, 1983). Glutathione is present in a relatively high concentration (2 mol/g brain) in brain parenchymal cells (Folbergrova et al, 1979), and its depletion causes a serious disorder in the CNS (Skullerud et al, 1980;Herrera et al, 2001). L-Cys is usually transported by a neutral amino acid transporter, such as system L, which is present at the BBB (Smith et al, 1987;Boado et al, 1999).…”

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confidence: 99%

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Enhancement of l-Cystine Transport Activity and Its Relation to xCT Gene Induction at the Blood-Brain Barrier by Diethyl Maleate Treatment

Hosoya

Tomi

Ohtsuki

et al. 2002

J Pharmacol Exp Ther

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The purpose of the present study was to elucidate the mechanism of enhancement of L-cystine uptake at the blood-brain barrier (BBB). The uptake of [ 14 C]L-cystine and [ 3 H]L-glutamic acid (L-Glu) was determined using a mouse brain endothelial cell line (MBEC4) as an in vitro BBB model. The mRNA levels of L-cystine/L-Glu exchanger, system x c Ϫ , which consists of xCT and 4F2hc, were determined by quantitative real-time reverse transcription-polymerase chain reaction analysis. The [14 C]Lcystine uptake by MBEC4 cells appeared to be mediated via an Na ϩ -independent saturable process. The corresponding Michaelis-Menten constant (K m ) was 63.7 M. In the presence of L-Glu, there was competitive inhibition with an inhibition constant (K i ) of 83.5 M.[ 3 H]L-Glu uptake in the absence of Na ϩ was saturable with a K m of 48.1 M, and it exhibited competitive inhibition with a K i of 24.9 M in the presence of L-cystine. The mutual inhibition between L-cystine and L-Glu and the type of inhibition suggest that system x c Ϫ operates in MBEC4 cells. The xCT and 4F2hc mRNAs were expressed in MBEC4 cells and, following diethyl maleate (DEM) treatment, the xCT mRNA level and L-cystine uptake in MBEC4 cells were enhanced in parallel with an increase in DEM concentration (up to 500 M). Concomitantly, the glutathione concentration in MBEC4 cells was increased. In conclusion, system x c Ϫ -mediated L-cystine uptake takes place in MBEC4 cells. L-Cystine transport via system x c Ϫ at the BBB is likely to be induced under oxidative stress conditions following DEM treatment due to enhanced transcription of the xCT gene.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Enhancement of l-Cystine Transport Activity and Its Relation to xCT Gene Induction at the Blood-Brain Barrier by Diethyl Maleate Treatment

Hosoya

Tomi

Ohtsuki

et al. 2002

J Pharmacol Exp Ther

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“…The first GSS-deficient patient diagnosed died at 28 years of age [37]. Examination of the brain showed focal lesions in the frontoparietal cortex, bilateral focal lesions in the visual cortex and thalamus, and selective atrophy of the granule cell layer of the cerebellum [38]. Other GSS-deficient patients who died during the neonatal period showed signs of cerebral necrosis, intrauterine hypoxia, and generalized cerebral atrophy with asymmetric and partly enlarged gyri, infection and haemorrhage.…”

Section: Pathology In Gss Deficiencymentioning

confidence: 98%

Glutathione synthetase deficiency

Njålsson

2005

Cell. Mol. Life Sci.

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Glutathione (GSH), one of the most important antioxidants in the eukaryotic organism, is synthesized in a two-step procedure where the last step is catalysed by the enzyme glutathione synthetase (GSS). GSS deficiency is inherited autosomal recessively, and patients with this disease can be divided into three groups, according to their clinical phenotype. Mildly affected patients have mutations affecting the stability of the enzyme, causing a compensated haemolytic anaemia; moderately affected patients have, in addition, metabolic acidosis; and severely affected patients also develop neurological defects and show increased susceptibility to bacterial infections. Moderately and severely affected patients have mutations that compromise the catalytic properties of the enzyme. 5-Oxoprolinuria appears in all three groups, but is more pronounced in the two latter groups. Today, no cure can be offered these patients; they are given vitamins C and E to boost their antioxidant levels, and bicarbonate to correct metabolic acidosis.

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“…Glutathione is a tripeptide composed of glutamate, cysteine, and glycine and plays an important role in cell protection against active oxygen and harmful materials (Meister and Anderson, 1983). Glutathione occurs in almost all cells and tissues, including central and peripheral nervous systems, and its depletion causes a serious disorder in these systems (Skullerud et al, 1980). Like other tissues, a reduced form of glutathione (GSH) is very predominant in the brain (Slivka et al, 1987h).…”

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confidence: 99%

Maintenance of Neuronal Glutathione by Glial Cells

Sagara

Miura

Bannai

1993

Journal of Neurochemistry

389

245

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Glutathione levels in neurons and glial cells were investigated in a neuronal-glial coculture and in separate cultures. Brain cell suspensions obtained from cerebral hemispheres of fetal rats were cultured, and after 5 days the glutathione content of this cell population, consisting mainly of neurons and astroglial cells, was 23.0 nmol/mg of cell protein, with a significantly high content in glial cells (28.0 nmol/mg of protein) in comparison with neurons (18.8 nmol/mg of protein). When the neurons and glial cells were separated and recultured in fresh medium, neuronal glutathione rapidly decreased, whereas glial glutathione remained unchanged. Cysteine is a rate-limiting precursor for glutathione synthesis, and its level was also decreased in neurons, but not in glial cells. Cysteine was taken up rapidly by both neurons and glial cells, but cystine was taken up only by glial cells. This accounts for the rapid decrease of glutathione in the cultured neurons, because the culture medium contains cystine, but not cysteine. It was also found that the cultured glial cells released cysteine into the medium. These results suggest that neurons maintain their glutathione level by taking up cysteine provided by glial cells.

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The cerebral lesions in a patient with generalized glutathione deficiency and pyroglutamic aciduria (5-oxoprolinuria)

Cited by 51 publications

References 19 publications

Enhancement of l-Cystine Transport Activity and Its Relation to xCT Gene Induction at the Blood-Brain Barrier by Diethyl Maleate Treatment

Enhancement of l-Cystine Transport Activity and Its Relation to xCT Gene Induction at the Blood-Brain Barrier by Diethyl Maleate Treatment

Glutathione synthetase deficiency

Maintenance of Neuronal Glutathione by Glial Cells

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