Amyotrophic lateral sclerosis, or ALS, attacks nerve cells called motor neurons in the brain and spinal cord, gradually leading to paralysis. Loss of function of an important gene, C9orf72, can affect communication between motor neurons and muscles in people with this disease. These results were revealed by Dr Kessen Patten’s team from the National Institute for Scientific Research (INRS) in the prestigious journal Communications biology.
A mutation in the C9orf72 gene is the main genetic cause of ALS. The mutation in C9orf72 consists of an expansion of a very unusual six base DNA sequence (GGGGCC) from a few copies (less than 20 in a healthy person) to more than 1000 copies. The mutation, leading in part to loss of function, may be responsible for 40 to 50% of hereditary cases of ALS and 5 to 10% of cases without a family history.
Dr. Patten’s team studied the loss of function of this gene in genetically modified zebrafish models. In their work, led by doctoral student Zoé Butti, the group noted symptoms similar to ALS, namely motor disorders, muscle atrophy, loss of motor neurons and mortality in individuals.
The study showed the effect of the loss of function induced by the mutation of the C9orf72 gene on the communication between motor neurons and muscles. “This synaptic dysfunction is observed in all people with the disease and occurs before the death of motor neurons,” noted the researcher and holder of the Anna Sforza Djoukhadjian Research Chair.
The research group also revealed the role of the gene on the TDP-43 protein (transactive response DNA binding protein 43) which plays an important role in ALS. The C9orf72 gene can affect the location of the TDP-43 protein in the cell. “In about 97% of patients with ALS, the TDP-43 protein is depleted from the nucleus and forms aggregates in the cytoplasm rather than being in the nucleus, as is the case in healthy people. want to study this relationship between the two proteins further, ”explained Professor Patten.
Now that the team has developed a model, it will be able to test therapeutic molecules. The goal is to find a drug to restore the synaptic connection between neurons and muscles. It can also lead to a therapeutic target for correcting the abnormality of the TDP-43 protein.