TRENTO, Italy – “New windows of knowledge on ALS that pave the way for innovative possibilities in diagnosis, prognosis, and therapy.” With these words, researcher Manuela Basso summarizes the significance of a newly published study that deepens understanding of Amyotrophic Lateral Sclerosis (ALS), particularly the molecular mechanisms behind its slower-progressing forms. The research appears in Brain, one of the leading journals in clinical neurology.
The study is the result of a large international collaboration involving 51 researchers from Italy, Spain, the United Kingdom, the United States, Lebanon, and Japan. It also leveraged advanced biomolecular research infrastructure at the University of Trento. Funding came from multiple sources, including Fondazione AriSla and several Italian national institutions.
A complex and highly variable disease
ALS is a progressive neurodegenerative disorder that affects motor neurons—the nerve cells responsible for controlling movement, including walking, speaking, swallowing, and breathing. While the disease shares common features, it is highly heterogeneous. Genetic mutations, molecular mechanisms, and disease progression can vary widely between patients, with survival ranging from months to decades.
Although no definitive cure exists, some treatments can slow disease progression. This study aims to better understand ALS variability by bridging basic and clinical research.
The role of glial cells
At the center of the research is the role of glia—supporting cells in the nervous system that nourish and protect neurons. These include astrocytes, oligodendrocytes, microglia, and ependymal cells.
The findings reveal that in slower-progressing ALS models, astrocytes and oligodendrocytes play a critical role in disease development. When the function of the protein TDP-43—altered in about 97% of ALS cases—is corrected, glial cells show different behaviors at different stages of the disease.
Early on, these cells lose their specialization (a process called de-differentiation), reducing their ability to support neurons. In later stages, they contribute to widespread inflammation.
A key molecular “culprit”
The study identifies a major driver behind these changes: a factor known as MYC. When overactive, MYC alters glial cell behavior, making them inflammatory and causing them to release small vesicles. Instead of supporting neurons, these vesicles increase neuronal vulnerability.
Importantly, similar vesicles were detected in patients’ cerebrospinal fluid. This suggests they could serve as biomarkers for diagnosing ALS and monitoring its progression. MYC itself may also represent a promising therapeutic target.
Toward personalized treatment
The findings open new avenues for research. Scientists now aim to determine whether glial de-differentiation and inflammation occur in all ALS patients and how these processes differ across individuals. Identifying reliable biomarkers could help classify patients into subgroups and guide more personalized therapies.
Another key focus will be timing—understanding when specific glial changes occur during the disease. Pinpointing these “windows” could allow for more targeted and effective treatment strategies.
Overall, the study marks a significant step toward unraveling ALS complexity and developing more precise approaches to its diagnosis and care.
Contact
Professor Manuela Basso – PhD
University of Trento
Phone: +39 0461 285219
Email: [email protected]