Distinctive sphingolipid patterns in chronic multiple sclerosis lesions

Podbielska, Maria; Szulc, Zdzisław M.; Ariga, Toshio; Pokryszko−Dragan, Anna; Fortuna, Wojciech; Bilińska, Małgorzata; Podemski, Ryszard; Jaśkiewicz, Ewa; Kurowska, Ewa; Yu, Robert K.; Hogan, Edward L.

doi:10.1194/jlr.ra120001022

Cited by 18 publications

(6 citation statements)

References 54 publications

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“…There is some evidence from previous studies in mice and humans that ceramides are increased in EAE [33,55] and MS [50,56,57] and contribute to the disruption of the BBB [21,58]. In a study using knockout mice or inhibition of acidic sphingomyelinase (ASM), it was suggested that high levels of ceramides are caused by over-activation of ASM [59,60], which produces ceramides in the lysosome via sphingomyelin degradation.…”

Section: Discussionmentioning

confidence: 99%

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

et al. 2021

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Depletion of the enzyme cofactor, tetrahydrobiopterin (BH4), in T-cells was shown to prevent their proliferation upon receptor stimulation in models of allergic inflammation in mice, suggesting that BH4 drives autoimmunity. Hence, the clinically available BH4 drug (sapropterin) might increase the risk of autoimmune diseases. The present study assessed the implications for multiple sclerosis (MS) as an exemplary CNS autoimmune disease. Plasma levels of biopterin were persistently low in MS patients and tended to be lower with high Expanded Disability Status Scale (EDSS). Instead, the bypass product, neopterin, was increased. The deregulation suggested that BH4 replenishment might further drive the immune response or beneficially restore the BH4 balances. To answer this question, mice were treated with sapropterin in immunization-evoked autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Sapropterin-treated mice had higher EAE disease scores associated with higher numbers of T-cells infiltrating the spinal cord, but normal T-cell subpopulations in spleen and blood. Mechanistically, sapropterin treatment was associated with increased plasma levels of long-chain ceramides and low levels of the poly-unsaturated fatty acid, linolenic acid (FA18:3). These lipid changes are known to contribute to disruptions of the blood–brain barrier in EAE mice. Indeed, RNA data analyses revealed upregulations of genes involved in ceramide synthesis in brain endothelial cells of EAE mice (LASS6/CERS6, LASS3/CERS3, UGCG, ELOVL6, and ELOVL4). The results support the view that BH4 fortifies autoimmune CNS disease, mechanistically involving lipid deregulations that are known to contribute to the EAE pathology.

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Section: Discussionmentioning

confidence: 99%

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

et al. 2021

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“…Recent studies suggest that lipid signatures can reveal potential biomarkers associated with disease progression, as well as provide novel information about pathomechanisms involved in progressive MS. Targeted sphingolipidomics have been employed to establish comprehensive SL profiles in chronic MS lesions [ 128 ]. Interestingly, our data on ex vivo SL analysis of postmortem tissues obtained from individuals with clinically diagnosed MS indicated distinctive lipid profiles in chronic MS lesions.…”

Section: Ms Progressionmentioning

confidence: 99%

New Insights into Multiple Sclerosis Mechanisms: Lipids on the Track to Control Inflammation and Neurodegeneration

Podbielska

O’Keeffe

Pokryszko−Dragan

2021

IJMS

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Multiple sclerosis (MS) is a central nervous system disease with complex pathogenesis, including two main processes: immune-mediated inflammatory demyelination and progressive degeneration with axonal loss. Despite recent progress in our understanding and management of MS, availability of sensitive and specific biomarkers for these both processes, as well as neuroprotective therapeutic options targeted at progressive phase of disease, are still being sought. Given their abundance in the myelin sheath, lipids are believed to play a central role in underlying immunopathogenesis in MS and seem to be a promising subject of investigation in this field. On the basis of our previous research and a review of the literature, we discuss the current understanding of lipid-related mechanisms involved in active relapse, remission, and progression of MS. These insights highlight potential usefulness of lipid markers in prediction or monitoring the course of MS, particularly in its progressive stage, still insufficiently addressed. Furthermore, they raise hope for new, effective, and stage-specific treatment options, involving lipids as targets or carriers of therapeutic agents.

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“…HexCers and SHexCers are structural lipids of myelin membrane and enriched in mature oligodendrocytes . In humans, the brain levels of HexCer and SHexCer (measured in the CSF) change during brain aging and in a number of pathological conditions such as multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease. − …”

Section: Discussionmentioning

confidence: 99%

Age-Related Neurometabolomic Signature of Mouse Brain

Chen

Lee

Truong

et al. 2021

ACS Chem. Neurosci.

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Neurometabolites are the ultimate gene products in the brain and the most precise biomolecular indicators of brain endophenotypes. Metabolomics is the only “omics” that provides a moment-to-moment “snapshot” of brain circuits’ biochemical activities in response to external stimuli within the context of specific genetic variations. Although the expression levels of neurometabolites are highly dynamic, the underlying metabolic processes are tightly regulated during brain development, maturation, and aging. Therefore, this study aimed to identify mouse brain metabolic profiles in neonatal and adult stages and reconstruct both the active metabolic network and the metabolic pathway functioning. Using high-throughput metabolomics and bioinformatics analyses, we show that the neonatal mouse brain has its distinct metabolomic signature, which differs from the adult brain. Furthermore, lipid metabolites showed the most profound changes between the neonatal and adult brain, with some lipid species reaching 1000-fold changes. There were trends of age-dependent increases and decreases among lipids and non-lipid metabolites, respectively. A few lipid metabolites such as HexCers and SHexCers were almost absent in neonatal brains, whereas other non-lipid metabolites such as homoarginine were absent in the adult brains. Several molecules that act as neurotransmitters/neuromodulators showed age-dependent levels, with adenosine and GABA exhibiting around 100- and 10-fold increases in the adult compared with the neonatal brain. Of particular interest is the observation that purine and pyrimidines nucleobases exhibited opposite age-dependent changes. Bioinformatics analysis revealed an enrichment of lipid biosynthesis pathways in metabolites, whose levels increased in adult brains. In contrast, pathways involved in the metabolism of amino acids, nucleobases, glucose (glycolysis), tricarboxylic acid cycle (TCA) were enriched in metabolites whose levels were higher in the neonatal brains. Many of these pathways are associated with pathological conditions, which can be predicted as early as the neonatal stage. Our study provides an initial age-related biochemical directory of the mouse brain and warrants further studies to identify temporal brain metabolome across the lifespan, particularly during adolescence and aging. Such neurometabolomic data may provide important insight about the onset and progression of neurological/psychiatric disorders and may ultimately lead to the development of precise diagnostic biomarkers and more effective preventive/therapeutic strategies.

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Distinctive sphingolipid patterns in chronic multiple sclerosis lesions

Cited by 18 publications

References 54 publications

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

Sapropterin (BH4) Aggravates Autoimmune Encephalomyelitis in Mice

New Insights into Multiple Sclerosis Mechanisms: Lipids on the Track to Control Inflammation and Neurodegeneration

Age-Related Neurometabolomic Signature of Mouse Brain

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