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.

Bioprospection of Natural Sources of Polyphenols with Therapeutic Potential for Redox-Related Diseases

“…However, clinical studies have provided conflicting evidence with some studies reporting negative effects or a lack of efficacy [ 49 , 50 , 51 ], whereas others reported amelioration of ALS symptoms [ 52 , 53 ]. More recently, in vivo preclinical evidence suggests that BCAA, tryptophan, and particularly arginine and proline metabolic pathways are associated with disease progression [ 54 ].…”

Global Metabolic Profiling Identifies a Pivotal Role of Proline and Hydroxyproline Metabolism in Supporting Hypoxic Response in Hepatocellular Carcinoma

“…However, a few studies have addressed whether AA metabolism is crucial for HCC tumor progression. Arginine and proline metabolisms are the central pathway for the biosynthesis of AAs from glutamate (24). Recently, proline metabolism has been shown to be critical for tumor Figure 4.…”

Promoting identification of amyotrophic lateral sclerosis based on label‐free plasma spectroscopy

“…In the aspect of pathway analysis, Patin et al highlighted that arginine-proline, tryptophan, and branched amino acid metabolic pathways were associated with ALS evolution. 24 In this study, we also identified several amino acid metabolism-related pathways, including phenylalanine-tyrosine-tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, and phenylalanine metabolism. The mechanisms underlying the disturbed amino acid metabolisms to ALS still need further investigations.…”