Sphingolipid Metabolism Is Dysregulated at Transcriptomic and Metabolic Levels in the Spinal Cord of an Animal Model of Amyotrophic Lateral Sclerosis

Henriques, Alexandre Cruz; Croixmarie, Vincent; Bouscary, Alexandra; Mosbach, Althéa; Keime, Céline; Boursier-Neyret, Claire; Walter, Bernard; Spedding, Michael; Loeffler, Jean‐Philippe

doi:10.3389/fnmol.2017.00433

Cited by 53 publications

(42 citation statements)

References 84 publications

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“…31 Altered sphingolipids included sphingomyelins, sphingosines, ceramides and hexosylceramides, which have been previously reported in ALS participant plasma, 14 15 25 CSF, 8 and spinal cord, 32 33 and ALS mouse models. [32][33][34][35] Targeting sphingolipid metabolism with sphingolipid inhibitors is at the forefront of cancer therapeutics, 36 and has been advocated as a possible treatment for Alzheimer's, Parkinson's and Huntington's disease. 37 38 Our study provides evidence that sphingolipid metabolism may similarly be targeted in ALS as a potential therapeutic opportunity.…”

Section: Figurementioning

confidence: 99%

Untargeted metabolomics yields insight into ALS disease mechanisms

Goutman

Boss

Guo

et al. 2020

J Neurol Neurosurg Psychiatry

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ObjectiveTo identify dysregulated metabolic pathways in amyotrophic lateral sclerosis (ALS) versus control participants through untargeted metabolomics.MethodsUntargeted metabolomics was performed on plasma from ALS participants (n=125) around 6.8 months after diagnosis and healthy controls (n=71). Individual differential metabolites in ALS cases versus controls were assessed by Wilcoxon rank-sum tests, adjusted logistic regression and partial least squares-discriminant analysis (PLS-DA), while group lasso explored sub-pathway-level differences. Adjustment parameters included sex, age and body mass index (BMI). Metabolomics pathway enrichment analysis was performed on metabolites selected by the above methods. Finally, machine learning classification algorithms applied to group lasso-selected metabolites were evaluated for classifying case status.ResultsThere were no group differences in sex, age and BMI. Significant metabolites selected were 303 by Wilcoxon, 300 by logistic regression, 295 by PLS-DA and 259 by group lasso, corresponding to 11, 13, 12 and 22 enriched sub-pathways, respectively. ‘Benzoate metabolism’, ‘ceramides’, ‘creatine metabolism’, ‘fatty acid metabolism (acyl carnitine, polyunsaturated)’ and ‘hexosylceramides’ sub-pathways were enriched by all methods, and ‘sphingomyelins’ by all but Wilcoxon, indicating these pathways significantly associate with ALS. Finally, machine learning prediction of ALS cases using group lasso-selected metabolites achieved the best performance by regularised logistic regression with elastic net regularisation, with an area under the curve of 0.98 and specificity of 83%.ConclusionIn our analysis, ALS led to significant metabolic pathway alterations, which had correlations to known ALS pathomechanisms in the basic and clinical literature, and may represent important targets for future ALS therapeutics.

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Section: Figurementioning

confidence: 99%

Untargeted metabolomics yields insight into ALS disease mechanisms

Goutman

Boss

Guo

et al. 2020

J Neurol Neurosurg Psychiatry

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“…Regarding ALS, a study by Henriquez et al, demonstrated a link between ALS severity and gene expressions or metabolite levels for sphingosine, ceramide (d18:1/26:0), SGPP2, SphK1, and UDP galactosyltransferase 8A (UGT8A) [154]. Shedding light on the therapeutic potential of the sphingolipid metabolism in ALS, Potenza et al, reported an improved neurological phenotype and an extended survival after fingolimod, a prodrug that becomes phosphorylated after application in vivo and acts as a receptor agonist against almost unanimously all S1PR-except for S1P 2 [155,156], administration in mSOD1 G93A mice [157].…”

Section: The Sphingolipid Metabolism In Neurodegenerative Disordersmentioning

confidence: 99%

“…The S1P lyase inhibitor LX3305 is currently being investigated in rheumatoid arthritis as an alternative to therapies with biologicals [273]. Conceptually, LX3305 s tentative application in neurological conditions where S1P is reduced/disturbed appears undoubtedly apprehensible, e.g., in neurodegenerative disorders such as Alzheimer's disease [134], Parkinson's disease [274], Huntington's disease [151,153], or amyotrophic lateral sclerosis [154]. Several diseases have been implicated in aberrant S1PR-specific signaling pathways.…”

Section: Insights Into Current and Future Therapeutic Perspectivesmentioning

confidence: 99%

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

Lucaciu

Brunkhorst

Pfeilschifter

et al. 2020

Cells

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Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, the S1P–S1PR axis is acknowledged in neurodegenerative, neuroinflammatory, and cerebrovascular disorders. Modulators of S1P signaling have enabled an immense insight into fundamental pathological pathways, which were pivotal in identifying and improving the treatment of human diseases. However, its intricate molecular signaling pathways initiated upon receptor ligation are still poorly elucidated. In this review, the authors highlight the current evidence for S1P signaling in neurodegenerative and neuroinflammatory disorders as well as stroke and present an array of drugs targeting the S1P signaling pathway, which are being tested in clinical trials. Further insights on how the S1P–S1PR axis orchestrates disease initiation, progression, and recovery may hold a remarkable potential regarding therapeutic options in these neurological disorders.

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“…Also, phospholipid metabolites were downregulated, such as the phosphatidylcholine (o‐22:1/20:4). However, there was an enrichment of glucosphingolipid metabolism in Tg‐SOD1 G86R mice (Henriques et al., ). Another study confirmed the downregulation of sphingolipids and the upregulation of glucosylceramides (Henriques et al., ).…”

Section: Introductionmentioning

confidence: 99%

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

et al. 2019

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Amyotrophic lateral sclerosis (ALS) is a rare and fatal neurodegenerative disorder. Two forms are recognized, familial (FALS) that accounts for 5–10% of ALS cases, and sporadic (SALS) that accounts for the rest. Early diagnosis of ALS is important because it improves their therapeutic efficacy. Current diagnosis is based on clinical assessment and requires approximately 12 months, leading to a significant delay in drug administration. Therefore, new methods are required for the earlier diagnosis of ALS. Screening for pathogenic variants in known ALS‐associated genes is already exploited as a diagnostic tool in ALS but cannot be applied for population‐based screening. New circulating biomarkers (proteins or small molecules) are needed for initial screening, whereas specific diagnostic methods can be applied to confirm the presence of pathogenic variants in the selected population subgroup. Lipids appear as promising biomarkers for population‐based screening and for monitoring disease progression. Genetic analysis can also assist in the prediction of disease progression by analyzing disease‐modifying genes, for example, EPHA4 and CHGB. Furthermore, molecular diagnosis will aid the stratification of ALS patients for improved pharmacological approaches. Here, we discuss current and novel diagnostic strategies and how they can be applied to revolutionize the field of ALS molecular diagnosis.

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Sphingolipid Metabolism Is Dysregulated at Transcriptomic and Metabolic Levels in the Spinal Cord of an Animal Model of Amyotrophic Lateral Sclerosis

Cited by 53 publications

References 84 publications

Untargeted metabolomics yields insight into ALS disease mechanisms

Untargeted metabolomics yields insight into ALS disease mechanisms

The S1P–S1PR Axis in Neurological Disorders—Insights into Current and Future Therapeutic Perspectives

New molecular diagnostic trends and biomarkers for amyotrophic lateral sclerosis

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