Amyotrophic lateral sclerosis (ALS) is a multifactorial disease characterised by progressive motor neuron degeneration and muscle paralysis. Despite currently used treatments, patients survive only 3-5 years after the initial diagnosis.

Weight loss is an important clinical feature of people with ALS at the time of diagnosis. With an estimated prevalence of 56%-62%, weight loss is defined as a relevant and independent prognostic factor. Several studies have reported that the course of the disease is unfavourable when patients lose weight rapidly or have a low body mass index at the time of diagnosis.

The international study, coordinated by Sapienza University of Rome and involving the departments of Physiology and Pharmacology, Chemistry and Technology of Drugs, Human Neuroscience and the University of Amsterdam, showed that the cytokine GDF15 is involved in the metabolic dysfunctions that characterise the disease.

Using a mouse model of the disease and samples from ALS patients, the researchers observed that GDF15 is highly expressed in peripheral blood and human tissue samples in the motor cerebral cortex, spinal cord and brainstem.

In particular, the study focused on the role of the GFRAL receptor, which is present in neurons in a specific region of the central nervous system, namely the area postrema and the nucleus tractus solitarius. The researchers showed that silencing the expression of GFRAL only in these regions resulted in a slowing of weight and fat tissue loss, improved motor function and increased survival in mice.

The study results point to an involvement of the GDF15-GFRAL axis in modulating the metabolic changes underlying weight loss and disease progression in ALS. The research highlights the importance of increasing the focus on nutritional and metabolic changes in patients to anticipate the diagnosis of the disease and to develop innovative therapeutic interventions.

“This study contributes to increasing our understanding of the mechanisms underlying amyotrophic lateral sclerosis”, says Cristina Limatola of the Department of Physiology and Pharmacology of Sapienza University. Indeed, we know that ALS can no longer be defined as a motor neuron disease, because numerous alterations have been described in the glial component and in the immune system before symptoms appear in patients and before neurodegenerative damage is measurable.Our discovery of the involvement of the cytokine GDF15 in the weight loss that precedes the manifestation of ALS symptoms confirms the importance of a holistic approach for an early diagnosis of the disease and the identification of new therapeutic targets”.

References:

Cocozza G., Busdraghi L. M., Chece G., Menini A., Ceccanti M., Libonati L., Cambieri C., Fiorentino F., Rotili D., Scavizzi F., Raspa M., Aronica E., Inghilleri M., Garofalo S., Limatola C., “GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis”, Brain, Behavior, and Immunity (2025) DOI: https://doi.org/10.1016/j.bbi.2024.12.010

Further Information

Cristina Limatola
Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza Universiy of Rome
cristina.limatola@uniroma1.it