Science

Patients with amyotrophic lateral sclerosis (ALS), also known as Charcot disease, gradually lose the use of their muscles following the death of the motor neurons which innervate them. Teams from Bordeaux have joined forces to reveal metabolic mechanisms that enable the motor neurons to temporarily resist their decline. These mechanisms explain certain paradoxical characteristics of the disease and open up new avenues for therapeutic research.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease, which manifests as gradual muscle paralysis. This paralysis is caused by the death of motor neurons which - from the brain to the spinal chord and from the spinal chord to the muscles - transmit nerve impulses. The pathophysiological mechanisms which trigger and maintain neuron degeneration are still poorly understood. The study of a genetic form of the disease, related to SOD1 gene mutation, has nevertheless opened up a research avenue: the protein synthesized from this mutated gene does not fold correctly. Instead, it binds to the mitochondria - the energy centers of the cells - causing their dysfunction from the embryonic stage.

A global approach

"Many studies suggest that the mitochondria are implicated not just in ALS but in several neurodegenerative conditions such as Alzheimer’s and Parkinson’s, as well as many forms of cancer, emphasizes Rodrigue Rossignol*. To find out more, we combined the study of mitochondrial function with an overall analysis of the metabolic pathways in order to better identify the mechanisms affected in this disease. We conducted this research on mouse motor neurons presenting the SOD1 mutation as well as skin cells (fibroblasts) from patients in whom the origin of ALS is unknown. The idea underlying this exploratory approach was that, if alterations are found in both models, they could correspond to central mechanisms in the disease."

Published in the March issue of Scientific Reports, the research conducted by the team of Rodrigue Rossignol, in collaboration with that of Gwendal Le Masson** and the reference center for ALS at the hospital of Bordeaux provides a deeper understanding of the biochemical mechanisms at play in ALS. The researchers showed that mitochondrial structure is abnormal in SOD1 mouse motor neurons and that this abnormality is accompanied by reduced energy efficiency: the amount of energy produced by the cells decreases for an equivalent oxygen consumption. This situation increases motor neuron energy demand, thereby bringing into play bioenergetic survival strategies.

Adaptation to delay motor neuron death

Through close analysis of SOD1 mouse motor neurons, the team showed that these cells very markedly increase their energy production from fatty acids. A metabolic pathway which is more efficient than that which uses glucose. Oxidation of the fatty acids then becomes crucial in order to keep the motor neuron alive. If this process is blocked, the motor neuron dies, whereas the effect on a healthy motor neuron would be minimal.

The downside is that this mode of energy production leads to the synthesis of substances – ketone bodies – which are toxic to the cell when present in excess. However, yet again, the motor neuron adapts by inhibiting the production pathway of the ketone bodies in favor of an alternative pathway, leading to the synthesis of cholesterol. "We obtain a consistent picture, with a diseased motor neuron which not just uses fatty acids in an attempt to compensate reduced mitochondrial energy production efficiency, but also modifies the transformation of an otherwise lethal end product", summarizes Rodrigue Rossignol.

This interpretation is backed by recent studies showing the presence of cholesterol deposits in the motor neurons of ALS patients. It would also explain why the hypermetabolism observed in some patients is associated (paradoxically) with decreased energy production. "The results of our research call into question the nutritional strategies sometimes envisaged to increase energy production – such as the supply of ketone bodies – which would impede mitochondrial adaptation efforts."

Following this research, the enzyme MTP (Mitochondrial Trifunctional Protein; HADHA/B), implicated in fatty acid oxidation and whose production increased in both models used by the researchers, appears as a potential biomarker of the disease. However, before it is used for the early diagnosis or monitoring of the condition, its utility first needs to be validated in a larger number of patients. In parallel, these findings open up many research avenues, whether in terms of identifying molecules able to help the mitochondria or in terms of exploring other cell functions that these researchers have also found to be altered in this disease.

Note

*unit 1211 Inserm/University of Bordeaux, Rare Diseases: Genetics and Metabolism, Dysmetabolism and neurodegeneration: Energy metabolism team, Bordeaux

**unit 1215 Inserm/University of Bordeaux, Glia-neuron interactions team, Neurocentre Magendie, Bordeaux

Source

M. Szelechowki et coll., Metabolic reprogramming in amyotrophic lateral sclerosis, Scientific Reports, édition du 2 mars 2018.