Metabolic Reprogramming in Amyotrophic Lateral Sclerosis
Sci Rep. 2018-03-02; 8(1):
DOI: 10.1038/s41598-018-22318-5
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1. Sci Rep. 2018 Mar 2;8(1):3953. doi: 10.1038/s41598-018-22318-5.
Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.
Szelechowski M(1)(2), Amoedo N(2)(3), Obre E(4), Léger C(1)(2), Allard L(1)(2),
Bonneu M(2)(5), Claverol S(2)(5), Lacombe D(2)(3), Oliet S(1)(2), Chevallier
S(1)(2), Le Masson G(6)(7), Rossignol R(8)(9).
Author information:
(1)INSERM U1215, Neurocentre Magendie, 33077, Bordeaux, cedex, France.
(2)Bordeaux University, 33000, Bordeaux, France.
(3)INSERM U1211, MRGM, 33000, Bordeaux, France.
(4)CELLOMET, Center of Functional Genomics (CGFB), 146 Rue Léo Saignat, 33000,
Bordeaux, France.
(5)Center of Functional Genomics (CGFB), Proteomic Facility, Bordeaux University,
33000, Bordeaux, France.
(6)INSERM U1215, Neurocentre Magendie, 33077, Bordeaux, cedex, France.
.
(7)Bordeaux University, 33000, Bordeaux, France. .
(8)Bordeaux University, 33000, Bordeaux, France.
.
(9)INSERM U1211, MRGM, 33000, Bordeaux, France. .
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.
DOI: 10.1038/s41598-018-22318-5
PMCID: PMC5834494
PMID: 29500423 [Indexed for MEDLINE]