Omics to Explore Amyotrophic Lateral Sclerosis Evolution: the Central Role of Arginine and Proline Metabolism
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In amyotrophic lateral sclerosis (ALS), motor neuron degeneration is associated with systemic metabolic impairment. However, the evolution of metabolism alteration is partially unknown and its link with disease progression has never been described. For the first time, we ran a study focused on (1) the evolution of metabolism disturbance during disease progression through omics approaches and (2) the relation between metabolome profile and clinical evolution. SOD1-G93A (mSOD1) transgenic mice (n = 11) and wild-type (WT) littermates (n = 17) were studied during 20 weeks. Metabolomic profile of muscle and cerebral cortex was analysed at week 20, and plasma samples were assessed at four time points over 20 weeks. The relevant metabolic pathways highlighted by metabolomic analysis were explored by a targeted transcriptomic approach in mice. Plasma metabolomics were also performed in 24 ALS patients and 24 gender- and age-matched controls. Metabolomic analysis of muscle and cerebral cortex enabled an excellent discrimination between mSOD1 and WT mice (p < 0.001). These alterations included especially tryptophan, arginine, and proline metabolism pathways (including polyamines) as also revealed by transcriptomic analysis and findings in ALS patients. Multivariate models performed to explain clinical findings in ALS mice, and patients were excellent (p < 0.01) and highlighted three main metabolic pathways: arginine and proline, tryptophan, and branched amino acid metabolism. This work is the first longitudinal study that evaluates metabolism alteration in ALS, including the analysis of different tissues and using a combination of omics methods. We particularly identified arginine and proline metabolism. This pathway is also associated with disease progression and may open new perspectives of therapeutic targets.
KeywordsAmyotrophic lateral sclerosis Metabolomics Transcriptomics Arginine Polyamine Biomarker
The authors thank Pr Hervé Watier for his invaluable assistance in preparing this manuscript. The authors thank Nowoczyn Marie who performed spectrometry analysis. The authors would especially like to thank the Fondation Brou de Laurières and the French “Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres maladies du motoneurone” (ARSLA) for their support of this project.
Franck Patin performed experiments involving animals, statistical analysis and interpretation of data and wrote the first draft of the manuscript. Philippe Corcia enrolled patients and revised the manuscript for important intellectual content. Patrick Vourc’h critically revised the manuscript for important intellectual content. Lydie Nadal-Desbarats supervised NMR analysis and critically revised the manuscript for important intellectual content. Thomas Baranek critically revised the manuscript for important intellectual content. Jean-François Goossens supervised mass spectroscopy analysis and revised the manuscript for important intellectual content. Sylviane Marouillat supervised experiments involving gene expression profiles. Anne-Frédérique Dessein supervised mass spectroscopy analysis and revised the manuscript for important intellectual content. Amandine Descat participated to mass spectroscopy analysis. Blandine Madji Hounoum revised the manuscript for important intellectual content. Clément Bruno participated experiments and revised the manuscript for important intellectual content. Samuel Leman supervised the rotarod experiments and revised the manuscript for important intellectual content. Christian Andres revised the manuscript for important intellectual content. Hélène Blasco analysed and interpreted data and critically revised the manuscript for important intellectual content.
AD Alzheimer disease, ADMA asymmetric dimethyl arginine, ALS amyotrophic lateral sclerosis, ALSFRS ALS Functional Rating Scale, BCAA branched chain amino acids, CSF cerebrospinal fluid, HPLC high-performance liquid chromatography, mSOD1 SOD1-G93A, MUFA monounsaturated fatty acids, NMDA N-methyl d-aspartic acid, NMR nuclear magnetic resonance spectroscopy, OPLS-DA orthogonal partial least square discriminant analysis, PCA principal component analysis, PDC pyruvate dehydrogenase complex, PDH pyruvate dehydrogenase, PUFA polyunsaturated fatty acids, QC quality control, ROS reactive oxygen species, SALS sporadic amyotrophic lateral sclerosis, SCD1 stearoyl-CoA desaturase, SDMA symmetric dimethyl arginine, SFA saturated fatty acids, VFC vital forced capacity, WT wild type
Compliance with Ethical Standards
Conflict of interest
The authors declare that no conflict of interest exists in relation to the present manuscript.
This study was supported by the Fondation Brou de Laurières (Périgueux, France).
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