Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia are serious neurodegenerative diseases for which therapeutic options are extremely limited. A new study shows that, in the most common genetic forms of these conditions, neuron degeneration can be prevented by correcting a precise molecular defect at the origin of the pathological process.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the destruction of upper and lower motor neurons, leading to progressive muscle weakness and, over time, paralysis.
Although relatively rare, with an incidence of approximately 1.6 cases per 100,000 adults, the disease has a major impact. Affecting nerve cells (motor neurons) in the brain and spinal cord, the disease causes their progressive degeneration and gradual loss of muscle control, leading to problems with walking, speaking, eating, and involuntary movements.
Currently, there is no curative treatment, and most of those diagnosed live between two and five years from the onset of symptoms.
Frontotemporal dementia is a neurodegenerative disease that mainly affects the frontal and temporal lobes of the brain, areas involved in behavior, language and emotional control. It is one of the most common forms of dementia in people under the age of 65.
Unlike Alzheimer’s, which is characterized by memory problems, fronto-temporal dementia involves the degeneration of the frontal and temporal lobes of the brain, affecting personality and behavior. The condition is progressive and, although it does not directly lead to death, it shortens life expectancy through the gradual loss of cognitive functions and associated complications.
Now, researchers from the National Center for Scientific Research (CNRS), in France, in collaboration with a team from Harvard University, have identified a specific molecular mechanism responsible for the most common genetic forms of ALS (also known as Lou Gehrig’s disease or Charcot’s disease) and frontotemporal dementia.
Neutralization of this common genetic abnormality prevented premature degeneration of neurons and motoneurons in several experimental cellular and animal models.
“Now we know where exactly we need to act in the genome to try to block a hereditary form of ALS,” explained Franck Martin, CNRS researcher and co-author of the study published on Thursday in the journal Sciencequoted from AFP.
In almost half of the familial cases of ALS and frontotemporal dementia, the same gene, C9ORF72, is affected. This gene contains repetitive sequences located in an intron – a segment of DNA that is normally removed before protein synthesis. In patients with these diseases, the elimination process is defective. The intron persists and is abnormally translated, which leads to the production of toxic proteins, which accumulate in neurons and motoneurons and cause their rapid degeneration.
The research team precisely identified the starting point of this aberrant translation: a codon, namely a sequence of three nucleotides, recognized by the ribosome as an atypical signal to initiate protein synthesis. The ribosome is the cell structure responsible for making proteins.
Targeted modification of this unique signal, by introducing a single mutation, is sufficient to completely stop the synthesis of toxic proteins involved in neuronal degeneration.
This strategy has been validated in mouse models and in motoneurons obtained from cells of ALS patients, after genome editing by CRISPR-Cas9 technology, a method of targeted DNA modification.
Under these conditions, the researchers managed to prevent the development of the disease in mice, and the lifespan of the cells was restored to values comparable to those of healthy cells.
The authors note that these results open the way to new therapeutic strategies that directly target the molecular cause of these neurodegenerative diseases, but there is still a long way to clinical application, and further research is needed.
