To date, 4 major genes have been identified as responsible for more than 50% of genetic cases of the disease. More than 30 genes have been implicated in familial forms of ALS.
The superoxide dismutase 1 (SOD1) gene was identified in 1993, and to date more than 150 different mutations have been found in patients. Since then, mutations have been identified in the TARDBP, FUS and C9ORF72 genes, which are involved in RNA metabolism (for TARDBP and FUS) and in the immune response (for C9ORF72). However, these mutations do not necessarily lead to the loss of function of these genes, making research all the more complex. Today, more than 70% of familial cases are associated with a known mutation, and research is continuing to find the mutations responsible for the remaining 30% of familial cases.
In sporadic forms of amyotrophic lateral sclerosis (ALS), which account for 90% of cases, there are probably predisposing genetic variants, i.e. genetic factors which increase the risk of developing the disease. The disease is considered to be multifactorial, and certain environmental and lifestyle factors could also contribute to the onset of the disease in predisposed individuals. To date, neither genetic nor environmental factors have been identified with any certainty.
Does the environment play a role in sporadic cases of the disease?
Studies have been carried out into the influence of environmental factors. In the 1950s, a large number of cases of a particular form of ALS were observed on the island of Guam. They were attributed to a toxin present in a micro-algae that colonised seeds eaten by bats, which were in turn eaten by the island’s inhabitants! Several cases of ALS have also been observed in American servicemen returning from the Gulf War. Certain toxic products are suspected but have not yet been identified. Finally, the risk of developing ALS is thought to be increased in certain sportspeople, particularly footballers and rugby players. Pesticides, shocks received during the practice of these sports, predisposition of the motor neurons of these top sportsmen and women? The hypotheses are manifold. These studies have the merit of raising the question of the role of the environment, and sporadic cases of ALS could well be the result of a combination of several factors.
At the Paris Brain Institute
Identifying new genetic mutations at the root of ALS
Stéphanie MILLECAMPS in Séverine BOILLEE’s team is looking to identify the genetic mutations that cause the disease. Thanks to the participation of the various ALS reference centres in France, researchers have been able to research the genetic mutations of 400 families affected by ALS and identify the genetic cause of the disease in 70% of cases. These studies make it possible to offer a molecular diagnosis to families who so wish, and also to include patients with a particular mutation in suitable clinical trials. There are still 30% of familial cases that need to be linked to causal mutations, and large-scale genetic analysis approaches are underway to achieve this.
European collaborative work has led to the identification of a new gene involved in ALS. Named TBK1, it is involved in the elimination of waste products inside cells and in the regulation of inflammation, demonstrating the importance of immune cells in the onset and probably the progression of the disease. Christian LOBSIGER in Séverine BOILLEE’s team (in collaboration with a German team), is modelling ALS linked to mutations in the TBK1 gene, in order to study these mechanisms and gain a better understanding of the disease.
Isabelle LE BER, in Alexandra DURR and Giovanni STEVANIN’s team, took part in an international study which, in 2018, identified a new causal gene in ALS, the KIF5A protein, which was already implicated in another central motor neurone disease: spastic paraplegia.