title: Omics to Explore Amyotrophic Lateral Sclerosis Evolution: the Central Role of Arginine and Proline Metabolism.
abstract: 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.
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France. patin.franck@gmail.com.|Laboratoire de Biochimie et Biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours, cedex 1, France. patin.franck@gmail.com.
authors: Franck
authors: F
authors: Patin
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France.|Fédération des CRCSLA Tours-Limoges (LITORALS), Tours, France.
authors: Philippe
authors: P
authors: Corcia
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France.|Laboratoire de Biochimie et Biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours, cedex 1, France.|Analyse des systèmes biologiques PPF, Université François Rabelais de Tours, Tours, France.
authors: Patrick
authors: P
authors: Vourc'h
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France.|Analyse des systèmes biologiques PPF, Université François Rabelais de Tours, Tours, France.
authors: Lydie
authors: L
authors: Nadal-Desbarats
authors: Centre d'étude des Pathologies Respiratoires, UMR 1100, INSERM, Université François Rabelais, Tours, France.
authors: Thomas
authors: T
authors: Baranek
authors: Centre Universitaire de Mesures et d'Analyses (CUMA), Université de Lille 2, Lille, France.
authors: Jean-François
authors: JF
authors: Goossens
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France.
authors: Sylviane
authors: S
authors: Marouillat
authors: Centre de Biologie et de Pathologie, CHRU de Lille, F-59000, Lille, France.
authors: Anne-Frédérique
authors: AF
authors: Dessein
authors: Centre Universitaire de Mesures et d'Analyses (CUMA), Université de Lille 2, Lille, France.
authors: Amandine
authors: A
authors: Descat
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France.
authors: Blandine
authors: B
authors: Madji Hounoum
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France.|Laboratoire de Biochimie et Biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours, cedex 1, France.
authors: Clément
authors: C
authors: Bruno
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France.
authors: Samuel
authors: S
authors: Leman
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France.|Laboratoire de Biochimie et Biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours, cedex 1, France.
authors: Christian R
authors: CR
authors: Andres
authors: Imagerie et Cerveau, UMR U930, INSERM, Université François Rabelais, Tours, France.|Laboratoire de Biochimie et Biologie moléculaire, Hôpital Bretonneau, CHRU de Tours, 2, Bd Tonnellé, 37044, Tours, cedex 1, France.
authors: Hélène
authors: H
authors: Blasco
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D055432:Metabolomics / Q000379:methods; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D011392:Proline / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics; D014364:Tryptophan / Q000378:metabolism
chemical_list: D014364:Tryptophan; D001120:Arginine; D011392:Proline; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: Amyotrophic lateral sclerosis; Arginine; Biomarker; Metabolomics; Polyamine; Transcriptomics