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A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis.

Wheeler D, Bandaru VV, Calabresi PA, Nath A, Haughey NJ - Brain (2008)

Bottom Line: Accumulating evidence suggests that even subtle perturbations in the lipid content of neurons and myelin can disrupt their function and may contribute to myelin and axonal degradation.The pattern of disturbance in lipid composition suggests a metabolic defect that causes sphingolipids to be shuttled to phospholipid production.Modelling the biophysical consequence of this change in lipid composition of NAWM indicated an increase in the repulsive force between opposing bilayers that could explain decompaction and disruption of myelin structure.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Richard T Johnson Division of Neuroimmunology and Neurological Infections, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

ABSTRACT
Maintaining the appropriate complement and content of lipids in cellular membranes is critical for normal neural function. Accumulating evidence suggests that even subtle perturbations in the lipid content of neurons and myelin can disrupt their function and may contribute to myelin and axonal degradation. In this study, we determined the composition and quantified the content of lipids and sterols in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) from control and multiple sclerosis brain tissues by electrospray ionization tandem mass spectrometry. Our results suggest that in active-multiple sclerosis, there is a shift in the lipid composition of NAWM and NAGM to a higher phospholipid and lower sphingolipid content. We found that this disturbance in lipid composition was reduced in NAGM but not in NAWM of inactive-multiple sclerosis. The pattern of disturbance in lipid composition suggests a metabolic defect that causes sphingolipids to be shuttled to phospholipid production. Modelling the biophysical consequence of this change in lipid composition of NAWM indicated an increase in the repulsive force between opposing bilayers that could explain decompaction and disruption of myelin structure.

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Reactive aldehyde levels of control and multiple sclerosis brain. (A) Reactive aldehyde array of grey and white matter showing individual hydroxynoneals that are decreased (red) and increased (green) in active-multiple sclerosis (Act) or inactive-multiple sclerosis (Ina) compared with control tissues. (B–C) Quantitative analysis of MRM spectra from grey (B) and white (C) matter showing levels of the lysine and histadine adducts of 4-HNE in multiple sclerosis and control brains. Data are mean ± SD from 8 control and 12 multiple sclerosis brains. ANOVA with Student–Neuman–Keuls post hoc comparison. ***P < 0.001 compared with control.
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Figure 5: Reactive aldehyde levels of control and multiple sclerosis brain. (A) Reactive aldehyde array of grey and white matter showing individual hydroxynoneals that are decreased (red) and increased (green) in active-multiple sclerosis (Act) or inactive-multiple sclerosis (Ina) compared with control tissues. (B–C) Quantitative analysis of MRM spectra from grey (B) and white (C) matter showing levels of the lysine and histadine adducts of 4-HNE in multiple sclerosis and control brains. Data are mean ± SD from 8 control and 12 multiple sclerosis brains. ANOVA with Student–Neuman–Keuls post hoc comparison. ***P < 0.001 compared with control.

Mentions: We next sought to determine if lipid peroxidation products accumulate in normal appearing brain tissues of multiple sclerosis. Qualitative analysis of the entire spectra clearly showed that lipid peroxidation is increased primarily in the white matter of multiple sclerosis (Fig. 5A). Quantitative analysis of two 4-hydroxynonenal (4-HNE) species showed no difference in grey matter of active- or inactive-multiple sclerosis compared with controls (Fig. 5B). However, in white matter of active- and inactive-multiple sclerosis, there were large accumulations of both the lysine and histadine adducts of 4-HNE (443 and 406%, respectively).Fig. 5


A defect of sphingolipid metabolism modifies the properties of normal appearing white matter in multiple sclerosis.

Wheeler D, Bandaru VV, Calabresi PA, Nath A, Haughey NJ - Brain (2008)

Reactive aldehyde levels of control and multiple sclerosis brain. (A) Reactive aldehyde array of grey and white matter showing individual hydroxynoneals that are decreased (red) and increased (green) in active-multiple sclerosis (Act) or inactive-multiple sclerosis (Ina) compared with control tissues. (B–C) Quantitative analysis of MRM spectra from grey (B) and white (C) matter showing levels of the lysine and histadine adducts of 4-HNE in multiple sclerosis and control brains. Data are mean ± SD from 8 control and 12 multiple sclerosis brains. ANOVA with Student–Neuman–Keuls post hoc comparison. ***P < 0.001 compared with control.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
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Figure 5: Reactive aldehyde levels of control and multiple sclerosis brain. (A) Reactive aldehyde array of grey and white matter showing individual hydroxynoneals that are decreased (red) and increased (green) in active-multiple sclerosis (Act) or inactive-multiple sclerosis (Ina) compared with control tissues. (B–C) Quantitative analysis of MRM spectra from grey (B) and white (C) matter showing levels of the lysine and histadine adducts of 4-HNE in multiple sclerosis and control brains. Data are mean ± SD from 8 control and 12 multiple sclerosis brains. ANOVA with Student–Neuman–Keuls post hoc comparison. ***P < 0.001 compared with control.
Mentions: We next sought to determine if lipid peroxidation products accumulate in normal appearing brain tissues of multiple sclerosis. Qualitative analysis of the entire spectra clearly showed that lipid peroxidation is increased primarily in the white matter of multiple sclerosis (Fig. 5A). Quantitative analysis of two 4-hydroxynonenal (4-HNE) species showed no difference in grey matter of active- or inactive-multiple sclerosis compared with controls (Fig. 5B). However, in white matter of active- and inactive-multiple sclerosis, there were large accumulations of both the lysine and histadine adducts of 4-HNE (443 and 406%, respectively).Fig. 5

Bottom Line: Accumulating evidence suggests that even subtle perturbations in the lipid content of neurons and myelin can disrupt their function and may contribute to myelin and axonal degradation.The pattern of disturbance in lipid composition suggests a metabolic defect that causes sphingolipids to be shuttled to phospholipid production.Modelling the biophysical consequence of this change in lipid composition of NAWM indicated an increase in the repulsive force between opposing bilayers that could explain decompaction and disruption of myelin structure.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Richard T Johnson Division of Neuroimmunology and Neurological Infections, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

ABSTRACT
Maintaining the appropriate complement and content of lipids in cellular membranes is critical for normal neural function. Accumulating evidence suggests that even subtle perturbations in the lipid content of neurons and myelin can disrupt their function and may contribute to myelin and axonal degradation. In this study, we determined the composition and quantified the content of lipids and sterols in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM) from control and multiple sclerosis brain tissues by electrospray ionization tandem mass spectrometry. Our results suggest that in active-multiple sclerosis, there is a shift in the lipid composition of NAWM and NAGM to a higher phospholipid and lower sphingolipid content. We found that this disturbance in lipid composition was reduced in NAGM but not in NAWM of inactive-multiple sclerosis. The pattern of disturbance in lipid composition suggests a metabolic defect that causes sphingolipids to be shuttled to phospholipid production. Modelling the biophysical consequence of this change in lipid composition of NAWM indicated an increase in the repulsive force between opposing bilayers that could explain decompaction and disruption of myelin structure.

Show MeSH
Related in: MedlinePlus