Metabolic Reprogramming in Amyotrophic Lateral Sclerosis

• Published in: Scientific reports Vol. 8; no. 1; pp. 3953 - 14
• Main Authors: Szelechowski, M., Amoedo, N., Obre, E., Léger, C., Allard, L., Bonneu, M., Claverol, S., Lacombe, D., Oliet, S., Chevallier, S., Le Masson, G., Rossignol, R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.03.2018; Nature Publishing Group
• Subjects: 13; 38/39; 631/80/642/1463; 631/80/642/333/1465; 82; Aminoacylation; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Animals; Bioenergetics; Cell adhesion; Cell Survival; Disease Models, Animal; Fatty Acids - metabolism; Fibroblasts; Fibroblasts - metabolism; Humanities and Social Sciences; Humans; Life Sciences; Metabolism; Mice; Mitochondria; Mitochondrial DNA; Mitochondrial uncoupling protein 2; Motor neurons; Motor Neurons - metabolism; multidisciplinary; Neurons and Cognition; Oxidation; Oxidation-Reduction; Oxidative Phosphorylation; Phosphorylation; Protein folding; Proteome; Science; Science (multidisciplinary); Skin; Skin - cytology; Skin - metabolism; Spinal cord; Spinal Cord - metabolism; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; tRNA; Uncoupling Protein 2 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-22318-5

Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients’ skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients’ skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.