New insights into ALS progression through glial cell behavior

All the core facilities of the Cibio Department of the University of Trento are involved in a study on ALS, co-funded by Fondazione AriSla, national organizations and various donors, to better understand the molecular mechanisms of slow-progressing cases. The study has been published in Brain.

"This work sheds new light on our knowledge of ALS, that opens the way to innovative diagnosis, prognosis and treatment opportunities." This is how Manuela Basso, professor of Biomolecular Sciences at the Department of Cellular, Computational and Integrative Biology of the University of Trento, sums up the contribution of the recently-published study for a better understanding of ALS and of the molecular mechanisms behind slow-progression cases. The study was published in Brain, one of the world's leading journals for clinical neurology.

Manuela Basso, corresponding author of the article, points out that the research is the result of collaboration between Italian and international institutes, as it involved 51 researchers from Italy, Spain, the United Kingdom, the United States, Lebanon and Japan and all the core facilities, the technological infrastructures available for biomolecular scientific research in the laboratories of the Cibio Department of the University of Trento. The work was funded by Fondazione AriSla and several national organizations, including the Ministry of University and Research, the Ministry of Health, pre-tax donations to the University of Trento and private donations.

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder that affects motor neurons, the nerve cells that control muscle movements, and the ability to walk, talk, swallow, breathe. While patients share common symptoms, ALS is distinctive in that it manifests in different forms, with genetic mutations, i.e. molecular mechanisms, that vary from person to person, and that can be rapid, measured in months, or slow and occur over decades.

Manuela Basso, Professor of Biomolecular Sciences at the Department of Cellular, Computational and Integrative Biology, University of TrentoThere is no cure, but for some forms today there are treatments that can slow down the progression of the disease. This study, which is the result of the cooperation between basic and clinical research, provides new anchors to better understand the clinical heterogeneity of ALS."

The focus of the study is the glia, the nervous system tissue made up of various cells – astrocytes, oligodendrocytes, microglia and ependymal cells – that nourish and protect neurons and ensure their proper functioning. The research aimed to analyse the role of the glia in the onset and evolution of ALS.

Manuela Basso adds more details: "The data observed in a slow progression model of ALS show the importance of astrocytes and oligodendrocytes in the pathogenesis of ALS. The altered functioning of the TDP-43 protein is observed in 97% of ALS patients; by correcting this protein, we found that the glial cells behave differently at different times of the disease: at the beginning of the disease they de-differentiate or, in other words, lose the specializations that allow them to support neurons. In the late stages, on the other hand, there is an increase in inflammation in all glial cells. It will be interesting to understand how the evolution of the disease varies in fast-progressing cases."

She also highlights the other results of the research: "Our study has discovered that a factor called 'MYC' is responsible for the abnormality of glial cells: when this factor is hyperactive, it pushes glial cells to change behaviour. Not only they become inflammatory, they also release small vesicles that, instead of feeding neurons, make them more vulnerable. We have also observed these signals in the cerebrospinal fluid of patients, and this leads us to hypothesize that the vesicles may be biomarkers to diagnose and monitor the evolution of the disease. At the same time, the 'MYC' factor could be a new molecular target to induce glial cells to support neurons again."

The results achieved by the study encourage us to continue our research work: "Our findings push us to move forward to understand whether glia de-differentiate and then become inflammatory in all patients and how we can identify these different processes in patients. At the same time, we must specifically verify the biomarkers that can help us group individuals with ALS into subgroups to define a more effective therapy," says Manuela Basso.

Finally, another aspect on which the research group will focus is the time span: "In order to adopt the best therapeutic approach, we will try to identify the activation windows of the glia, such as de-differentiation, proliferation and neuroinflammation."

Source:

University of Trento

Journal reference:

Fioretti, P. V., et al. (2026) MYC-driven gliosis impairs neuron-glia communication in amyotrophic lateral sclerosis. Brain. DOI: 10.1093/brain/awaf360. https://academic.oup.com/brain/article/149/5/1604/8266576