Laval University study reveals role of nervous system cell metabolism, combined with inflammation, in ALS-related neuronal degeneration
What if amyotrophic lateral sclerosis (ALS) was also a metabolic disease? That’s the question raised by a research team led by Chantelle Sephton, professor at Université Laval’s Faculty of Medicine and researcher at the CERVO research center. Their work on a mouse model suggests that the way nervous system cells use energy contributes to the death of motor neurons in the brain and spinal cord.
Reprogramming metabolism
In a healthy person, cells use glucose to function, but in a person with ALS, they turn to another source of energy: lipids. Professor Sephton reports that human studies showed a decline in glucose utilization in the brain up to 10 years before the first symptoms of the disease.
Her hypothesis is that mitochondria, the "energy powerhouses" of cells, are reprogrammed to use fats, which accumulate in the form of lipid droplets. However, the mitochondria are unable to use them efficiently, generating an overabundance of oxidized lipids that are highly unstable and damage cells. "A chain reaction occurs, as their presence causes damage to DNA, proteins and cell membranes", says Chantelle Sephton.
The team therefore tested a drug, arimoclomol, developed for diabetics to reduce lipids in the central nervous system. "In our mouse model, mitochondria could use lipids more easily to generate energy in the cells of the nervous system. There was no longer any accumulation of toxic lipids, and cognitive and motor functions improved", says Professor Sephton.
Professor Sephton warns that arimoclomol has already been the subject of a clinical trial in people with ALS, but the drug showed no beneficial effect. "We’re not saying to use this molecule to treat the disease, but we’re showing, in mice, that it can have an effect on lipid utilization to bring about a metabolic change."
Inflammation, a vicious circle
In their mouse model, the scientists observed that the presence of inflammation, identified as a factor in the disease in a previous study , aggravated droplet accumulation. "When there’s a lot of inflammation, you see more lipid droplets in the cells. This creates a vicious circle where cellular stress further fuels inflammation and lipid toxicity, accelerating neuronal death", explains the professor.
Chantelle Sephton’s work suggests a connection between metabolism and inflammation, but she doesn’t know the causal link. The ideal, she believes, would be to tackle both at the same time by cutting inflammation to reduce the accumulation of lipid droplets, while restoring the cells’ ability to use fat.
"Our data support the hypothesis that ALS is not just a disease of neurons, but also a disease of metabolism. We have identified other potential targets for trying to treat this disease", concludes Chantelle Sephton.
The study was published in the journal Brain. The Université Laval-affiliated signatories are Laetitia Marcadet, Mari Carmen Pelaez, Antoine Desmeules, Jeanne Serrano, Sahara Khademullah, Elahe Parham, Jorge Soliz, Paul Dutchak and Chantelle Sephton. They collaborated with scientists from McGill University, the University of Alberta and King’s College, UK.
