Université de Strasbourg

Fellows Seminar - What causes weight loss in Charcot’s disease?

September 21, 2021
From 15:30 until 17:00
Strasbourg (FR)

MCH staining on a hypothalmus slice from a mouse with ALS

By Luc Dupuis, 2019 Fellow

Amyotrophic lateral sclerosis (ALS, aka Lou Gehrig’s disease or Charcot’s disease) is an adult onset neurodegenerative disease that leads to death within a few years after the onset of symptom through a progressive paralysis and respiratory insufficiency.

ALS is partly inherited, and there are currently more than 30 different genes that have been associated to the disease.

Among the symptoms of ALS patients, weight loss occurs early, usually 10 to 15 years before the onset of motor troubles, and is negatively correlated with survival. Importantly, increasing caloric intake, thus slowing down weight loss, allows to increase the lifespan of mouse models and increases survival of fast-progressing ALS patients. However, the neuroanatomical substrate of weight loss in ALS remains unknown.

Our USIAS funded project explores the hypothesis that weight loss is driven by dysfunction of a small brain region called the hypothalamus. The hypothalamus is a key player in the control of energy metabolism, and our previous research has shown that it is atrophied in ALS patients, long before motor onset. We have identified one neuronal type, Melanin-concentrating hormone (MCH) expressing neurons, as degenerating in both mouse models and ALS patients, and demonstrate that MCH intracerebro-ventricular administration rescues weight loss. Intriguingly, the effects of MCH appear largely sex-dependent, with female ALS mice displaying vast changes in multiple metabolic parameters, while male ALS mice, although showing increased weight gain upon MCH, remained largely resistant to metabolic rewiring. To determine whether these sex-dependent effects were translationally relevant, we re-analysed our previous clinical results according to sex, and observed that male presymptomatic ALS gene carriers displayed hypothalamic atrophy that was not observed in female presymptomatic gene carriers. Strikingly, high caloric nutritional supplementation appeared much more efficient in female ALS patients than in male ALS patients. In all, we show that weight loss is, at least in part, driven by hypothalamic alterations that are different between men and women. These results have strong consequences for the nutritional therapeutic strategies for ALS.

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