ALS occurs in adults (40-80 years old) and will develop, in 3 to 5 years, to complete paralysis and patient death by respiratory muscle paralysis.
Approximately 2/3 of patients with ALS show the spinal form of the disease (limb injuries) characterised by weakness and muscular loss in lower and upper limbs.
Gradually, stiffness develops in atrophied limbs, affecting manual dexterity and gait. Patients in whom the first symptoms of the disease are bulbar signs (1/3 of cases) have a difficulty in speaking and swallowing. The limb symptoms can occur almost simultaneously with bulbar symptoms or in most cases 1 to 2 years afterwards. Paralysis is progressive and leads to respiratory failure leading to death within 2 to 5 years, with a median survival time of 3 years (50% of patients).
It is a neurodegenerative disease affecting motor systems. Progressive paralysis is the result of degeneration, namely, a motor neuron cell death, nerve cells controlling voluntary muscles. It is an incurable disease which is not cured today.
Most ALS cases are sporadic forms, namely, with no family history, but about 10% of patients have one (or more) relative(s) who has/have already been affected by the same disease, and these cases are known as family forms.
Amyotrophic Lateral Sclerosis, or ALS, affects approximately 8 000 patients in France. It affects both genders with slight male predominance.
There is currently no treatment capable of stopping the progression of the disease. Only Riluzole, identified by professor Vincent Meininger at the Pitié-Salpêtrière hospital, is capable of extending patients’ lives for a few months. It is probably a motor neuron neuroprotective molecule, with a poorly known mechanism of action.
However, a great deal of progress has been made in the symptomatic treatment area to improve patients’ well-being : in the case of bulbar weakness, radiation therapy can reduce hyper-salivation by targeting salivary glands ; masks provide better patient ventilation. Speech therapy and physical therapy aim at maintaining remaining muscle functions.
Institut du Cerveau – ICM RESPONSES
TOPICS AND RESEARCH TEAMS
- Identify risk factors in order to be able to model the disease and elucidate the mechanisms involved in its progression with Séverine Boillée and Edor Kabashi’s teams.
- Identify the factors involved in the evolution of the disease and find new therapeutic targets with Bertrand Fontaine and Sophie Nicole’s team.
- Slow down ALS progression through understanding the role of inflammatory processes in motor neuron degeneration with Séverine Boillée’s team.
- Discover new treatments through, on the one hand, the development of a zebrafish model by Edor Kabashi’s team and on the other hand, of human motor neuron cultures generated from induced pluripotent stem cells derived from patients by
- Séverine Boillée’s team. These models are used to test different molecules to fight the disease.
Discovery of a new gene
Many genetic factors can cause ALS, the most common being C9orf72 and SOD1 genes. Stéphanie Millecamps in Séverine Boillée’s team has participated in the discovery of a new gene, TBK1, identified in familial forms of ALS with or without frontotemporal dementias. Loss of function of TBK1 protein, related to the immune system and autophagy (degradation of abnormal proteins within the cell), is one of the mechanisms which could be involved in the disease and lead to neuron death. The discovery of this gene enables to better understand the mechanisms involved in the disease and improve diagnostic tools.
Identification of a factor toxic to motor neurons
In ALS, as in all neurodegenerative diseases, an immune response to protect the body is observed in the central nervous system. How does this immune reaction become harmful, and participates in neuron death ? Séverine Boillée’s team has shown that, in the case of a mutation causing ALS, cells responsible for nervous system protection release toxic factors leading to motor neuron death. By blocking the release of these factors, researchers are able to slow the progression of ALS in an experimental model. The emphasis of this mechanism of action opens the way for the development of new therapeutic strategies.
Protein degradation defect causing ALS ?
Edor Kabashi’s team has developed the first zebrafish model expressing a mutation in Sqstm1 gene. Inactivating this gene leads to a loss of fish motor functions and motor neuron deficit, which imitates ALS symptoms. Using this model, researchers have demonstrated that autophagy stimulation ( degradation of abnormal proteins within the cell) restores normal motor skills in the zebra fish. Autophagy dysregulation may cause ALS. These very encouraging results may represent a therapeutic perspective for patients with ALS. This model also allows to test candidate molecules
Targeting neuromuscular junction, hope for ALS ?
Gaelle Bruneteau in Bertrand Fontaine and Sophie Nicole’s team, and her collaborators, have shown that there were neuromuscular junction early morphologic defects in ALS patients. These defects may significantly contribute to motor function impairment. Neuromuscular junction is the link between motor neuron and muscle fiber, and its activation makes muscle contraction possible. In addition, overexpression of a protein at the muscle level, Nogo-A, was associated with more emphasized neuromuscular junction defects with a more frequent loss of contact between motor nerve and muscle ; and a worse functional prognosis. Nogo-A muscular accumulation, observed in patients with ALS may therefore be a factor of poor prognosis.
Identify biomarkers to predict the progression of the disease
PULSE ARS1 national multicentric study, funded by the ARSLA, coordinated by David Devos and conducted on a cohort of 1 000 patients, aims to identify disease progression biomarkers. This study aims to better clarify different clinical symptoms of the disease, follow the specific developments of each of them and determine predictive parameters and prognosis of the disease progression (biomarkers). It will enable the establishment of a national data bank gathering parameters characterising people evolving slowly and people evolving rapidly, and eventually be able to predict the evolution of the disease for each patient.
Identify biomarkers to characterise motor neuron diseases
A study coordinated by Pierre-François Pradat has compared the gene expression profile at the muscle level between patients with ALS, with different motor neuron diseases (Kennedy syndrome, spinal muscular atrophy) and healthy subjects. The purpose is to establish a “molecular signature” of different sub-types of motor neuron diseases in order to be able to diagnose them accurately and better adapt care.
Make human motor neurons from patient skin fibroblasts
Lucette Lacomblez is coordinating a study consisting in the establishment of a collection of skin cells (fibroblasts) from 30 patients with ALS. Delphine Bohl in Séverine Boillée’s team then generates induced pluripotent stem cells, called iPS, from these fibroblasts, and differentiates these iPS in pure motor neuron cultures. The purpose of this study is to investigate and compare motor neuron defects of patients with different genetic mutations, in order to better understand the evolution of the disease and the need for new models to test the efficacy of therapeutic molecules.
Improve walking performance
A study conducted on 31 patients, coordinated by Pierre-François Pradat and in collaboration with Giovanni Marco (CeRSM lab, Nanterre) has assessed walking and postural control using multidisciplinary approach combining neurophysiological and neuroimaging analyses. The purpose of this study is to develop therapeutic strategies (pharmacological and rehabilitation therapies) to improve walking performance in patients with ALS.
A tool to write with eyes
As a result of their disability, patients with ALS have difficulties to express themselves. In collaboration with Jean Lorenceau, a pilot study, aiming at teaching patients with significant motor disabilities how to write with their eyes, through a device allowing to draw and write using eye movement, has been carried out at the Therapeutic Evaluation Center by Timothee Lenglet.