The immune system appears to play a leading role in amyotrophic lateral sclerosis type 4, juvenile ALS caused by mutations in the senataxin gene (SETX, which contains information for the production of a protein involved in RNA transcription). The progression of the disease would in fact be linked to the dysfunction of a type of lymphocytes particularly active in patients with this form of ALS. The discovery is due to researchers from the Microbiology Department of the Icahn School of Medicine at Mount Sinai in New York, who coordinated the study, involving the NeMO Clinical Center in Milan.
The discovery, also thanks to the study of an Italian family
The researchers arrived at these results, published in Nature, after the first studies on ALS 4 conducted in the USA and after that in 2010 the NeMo Center in Milan, in collaboration with the laboratory of Medical Genetics of the ASST Grande Ospedale Metropolitano Niguarda, identified the first Italian family affected by the disease. From the diagnosis of the first patient, made after fifteen years of living with the disease, the reconstruction of the parental genetic history of the whole family has provided the first clues on the correlation between the mutation and the dysfunction of the immune system.
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Research
“Cells that do not express the senataxin protein produce more inflammatory molecules,” explains a Salute and New York Laura Campisi, PhD and Assistant Professor who at Mount Sinai co-directed the project together with Ivan Marazzi, PhD and Associate Professor. “And since senataxin itself changes in people with ALS 4, we wondered if there could be any disease-related dysfunctions in the immune system of these patients. To understand this, we conducted studies on mouse models, where we noticed that the loss of motor skills only occurs if the SETX gene mutation is expressed in both central nervous system and immune system cells. Hence the suggestion that the immune system and inflammatory mechanisms could play a role in the disease “.
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The researchers then performed a thorough analysis of the immune system in the mice and patients. “In this phase we have identified those anomalies of the lymphocyte system that would confirm our hypotheses”, continues Campisi: “In both animals and patients, in fact, a high concentration of T CD8, the cells lymphocytes of the immune system that are activated to defend the organism from attack by pathogens. In particular, we have noticed that the increase in a sub-population of these cells, called TEMRA, directly correlates with the progression of the disease “.
The next steps
Now we need to better understand the role of lymphocyte cells in this form of ALS, that is, how they behave at the level of the central nervous system: if there is only a correlation or if they have an active role in the disease. If this were the case – continues the researcher – it would be good news, because the targets towards which to direct new therapies would be clear. But there is also another goal. “We want to verify if what we have noticed in SLA 4 also affects the other forms. That is, whether the immune system and lymphocyte cells play the same role in other types of ALS, and what are the differences between them. This, in fact, would make it possible to study tailor-made treatments for specific subgroups of patients “. Another aspect that emerges from the research could instead lead to advantages in clinical practice. The dysfunction of the CD8 T lymphocyte cells – which could be used to understand the evolution of the disease – is in fact observable in the peripheral blood, more easily accessible than in the cerebrospinal fluid.
The right therapy for the right patient
Type 4 ALS begins in late childhood or adolescence (6-21 years) and progresses slowly, with signs of spasticity and muscle atrophy, making mobility difficult. There is currently no cure. “Understanding the causes of the disease represents an important step towards identifying the correct therapeutic target – he concludes Federica Cerri, manager of the ALS area of the NeMO Clinical Center in Milan – It is therefore essential to continue and invest in research, trying to summarize and critically analyze the information acquired over the years. Only by better clarifying what defines and characterizes the different types of ALS will it be possible to identify the right therapy for the right patient ‘”.